Activation of the dorsal septum increases alcohol consumption in male C57BL/6J mice

Haun, Harold L.; D’Ambrosio, Shannon; Pati, Dipanwita; Taxier, Lisa R.; Kash, Thomas L.

doi:10.1016/j.addicn.2022.100023

Cited by 3 publications

(8 citation statements)

References 70 publications

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“…Mice underwent intracranial stereotactic surgery at 8-12 weeks of age using procedures previously described 27 . Briefly, mice were anesthetized with isoflurane (2%) and a Hamilton Neuros syringe was used to infuse adeno-associated virus (AAV) into either the LS, LH, or SuM at a flow rate of 0.05 uL/min, followed by a 5 min diffusion period, and 5 min retraction.…”

Section: Methodsmentioning

confidence: 99%

“…The LS is generally involved in binge-like alcohol consumption 27 and alcohol withdrawal is associated with increased excitability in various brain regions and cell types associated with negative affect [47][48][49][50][51] . Because LS Pnoc is responsive to aversive stimuli, we sought to assess LS Pnoc excitability during withdrawal from binge drinking when signs of negative affect emerge using whole-cell patch-clamp electrophysiology.…”

Section: Binge Drinking Increases Excitability Of Ls Pnocmentioning

confidence: 99%

“…We have recently shown that activation of the dorsal septum (dSep; comprising the LS and dorsal tip of the medial septum) is sufficient to increase alcohol and sucrose intake in males, and increase locomotor activity 27 . Here we report that more discrete isolation of LS Pnoc revealed a selective contribution to alcohol drinking, and the ability of this population to affect alcohol intake was not influenced by biological sex.…”

Section: Aud Neurocircuitry: Role For the Lateral Septum In Binge Dri...mentioning

confidence: 99%

“…However, no studies to date have isolated and examined a nociceptin-expressing population in a preclinical model of AUD, driving the question of endogenous nociceptin involvement in excessive drinking behavior. The lateral septum (LS) is a site of interest given that it is enriched in Pnoc mRNA 22,23 , promotes drug seeking behavior [24][25][26] , and drives binge-like alcohol drinking in male mice 27 . Furthermore, the LS is situated as an integral node in addiction circuitry, interfacing directly with regions involved in binge drinking behavior such as the VTA, nucleus accumbens (NAc), and hypothalamus [28][29][30] .…”

Section: Introductionmentioning

confidence: 99%

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Septo-hypothalamic regulation of binge-like alcohol consumption by the nociceptin system

Haun,

Hernandez,

Yan

et al. 2024

Preprint

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High intensity alcohol drinking during binge episodes overwhelmingly contributes to the socioeconomic burden created by Alcohol Use Disorders (AUD). Novel interventions are needed to add to the current therapeutic toolkit and nociceptin receptor (NOP) antagonists have shown promise in reducing heavy drinking days in patients with an AUD. However, an endogenous locus of nociceptin peptide and discrete sites of NOP action underlying this effect remains understudied. Here we show that the lateral septum (LS), a region contributing to binge drinking, is enriched in neurons expressing mRNA coding for the nociceptin peptide (Pnoc). Pnoc-expressing neurons of the LS (LSPnoc) are tuned to stimuli associated with negative valence and display increased excitability during withdrawal from binge-like alcohol drinking. LSPnocactivation was found to have aversive qualities and also potentiates binge-like drinking behavior, suggesting a convergence of circuitry that promotes aversion and drives alcohol consumption. Viral mediated tracing and functional assessment of LSPnocprojection fields revealed GABAergic synapses locally within the LS, and downstream within the lateral hypothalamus (LH) and supramammillary nucleus (SuM). Genetic deletion of NOP from the LS attenuated binge-like alcohol intake in male mice while NOP deletion from the LH and SuM decrease alcohol intake in females. Together, these findings are the first to demonstrate an endogenous population of nociceptin-expressing neurons that contributes to alcohol consumption and identifies sex-dependent modulation of alcohol drinking by NOP.

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Section: Methodsmentioning

confidence: 99%

Section: Binge Drinking Increases Excitability Of Ls Pnocmentioning

confidence: 99%

Section: Aud Neurocircuitry: Role For the Lateral Septum In Binge Dri...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Septo-hypothalamic regulation of binge-like alcohol consumption by the nociceptin system

Haun,

Hernandez,

Yan

et al. 2024

Preprint

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show abstract

“…That is, the LS gates both positive and negative motivation 7 and is thought to be a key structure involved in substance use disorders [8][9][10][11][12][13] . Indeed, rodents will self-administer opioids directly into the LS, which suggests that there is a subset of opioid-sensitive neurons in the LS that modulate positive reinforcement [14][15][16] .…”

Section: Introductionmentioning

confidence: 99%

Opioid-driven disruption of the septal complex reveals a role for neurotensin-expressing neurons in withdrawal

Simon,

Fleming,

Senthilkumar

et al. 2024

Preprint

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Because opioid withdrawal is an intensely aversive experience, persons with opioid use disorder (OUD) often relapse to avoid it. The lateral septum (LS) is a forebrain structure that is important in aversion processing, and previous studies have linked the lateral septum (LS) to substance use disorders. It is unclear, however, which precise LS cell types might contribute to the maladaptive state of withdrawal. To address this, we used single-nucleus RNA-sequencing to interrogate cell type specific gene expression changes induced by chronic morphine and withdrawal. We discovered that morphine globally disrupted the transcriptional profile of LS cell types, but Neurotensin-expressing neurons (Nts; LS-Nts neurons) were selectively activated by naloxone. Using two-photon calcium imaging and ex vivo electrophysiology, we next demonstrate that LS-Nts neurons receive enhanced glutamatergic drive in morphine-dependent mice and remain hyperactivated during opioid withdrawal. Finally, we showed that activating and silencing LS-Nts neurons during opioid withdrawal regulates pain coping behaviors and sociability. Together, these results suggest that LS-Nts neurons are a key neural substrate involved in opioid withdrawal and establish the LS as a crucial regulator of adaptive behaviors, specifically pertaining to OUD.

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Orexinergic lateral hypothalamus (LH) projections to medial septum (MS) modulate ethanol-induced sedation in male and female mice and binge-like ethanol drinking in male mice only

Bendrath,

Cook,

Knapp

et al. 2024

Alcohol

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Activation of the dorsal septum increases alcohol consumption in male C57BL/6J mice

Cited by 3 publications

References 70 publications

Septo-hypothalamic regulation of binge-like alcohol consumption by the nociceptin system

Septo-hypothalamic regulation of binge-like alcohol consumption by the nociceptin system

Opioid-driven disruption of the septal complex reveals a role for neurotensin-expressing neurons in withdrawal

Orexinergic lateral hypothalamus (LH) projections to medial septum (MS) modulate ethanol-induced sedation in male and female mice and binge-like ethanol drinking in male mice only

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