The use of chemogenetic approaches in alcohol use disorder research and treatment

Cheng, Yidong; Wang, Jun

doi:10.1016/j.alcohol.2018.05.012

Cited by 12 publications

(5 citation statements)

References 69 publications

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“…This approach relies upon a method of delivering paired electromagnetic pulses through multiple electrodes at an ultra-low frequency (≤1Hz) to induce STDP onto D1-MSNs of the direct pathway. The results described here are consistent with an emerging body of literature suggesting that reducing alcohol-related D1-MSN hyperactivity or increasing D2-MSN hypoactivity reduces alcohol seeking and consumption 17,[20][21][22][23][24][25][26][27][28][29] . We tested the hypothesis that GPi/ACC ULF-STDP(+) will selectively decrease alcohol consumption and D1-MSN synaptic strength in a mouse model of AUD (Figure 7).…”

Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

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An ultra-low frequency spike timing dependent plasticity-based approach for treating alcohol use disorder

Anders

Boschen

Luján

2021

Preprint

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Alcohol use disorder (AUD) is a chronic relapsing brain disorder characterized by an impaired ability to stop or control alcohol consumption despite adverse social, occupational, or health consequences. AUD affects nearly one-third of adults at some point during their lives, with an associated cost of approximately $249 billion annually in the U.S. alone. The effects of alcohol consumption are expected to increase significantly during the COVID-19 pandemic, with alcohol sales increased by approximately 54%, potentially exacerbating health concerns and risk-taking behaviors. Unfortunately, existing pharmacological and behavioral therapies for AUD have historically been associated with poor success rates, with approximately 40% of individuals relapsing within three years of treatment. Pre-clinical studies have shown that chronic alcohol consumption leads to significant changes in synaptic function within the dorsal medial striatum (DMS), one of the brain regions associated with AUD and responsible for mediating goal-directed behavior. Specifically, chronic alcohol consumption has been associated with hyperactivity of dopamine receptor 1 (D1) medium spiny neurons (MSN) and hypoactivity of dopamine receptor 2 (D1) MSNs within the DMS. Optogenetic, chemogenetic, and transgenic approaches have demonstrated that reducing the D1/D2 MSN signaling imbalance decreases alcohol self-administration in rodent models of AUD. However, these approaches cannot be studied clinically at this time. Here, we present an electrical stimulation alternative that uses ultra-low (<=1Hz) frequency (ULF) spike-timing dependent plasticity (STDP) to reduce DMS D1/D2 MSN signaling imbalances by stimulating D1-MSN afferents into the GPi and ACC glutamatergic projections to the DMS in a time-locked stimulation sequence. Our data suggest that GPi/ACC ULF-STDP selectively decreases DMS D1-MSN hyperactivity leading to reduced alcohol consumption without evoking undesired affective behaviors in a two-bottle choice mouse model of AUD.

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

An ultra-low frequency spike timing dependent plasticity-based approach for treating alcohol use disorder

Anders

Boschen

Luján

2021

Preprint

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“…This approach relies upon a method of delivering paired electrical pulses through multiple electrodes at an ultra-low (≤1Hz) frequency (ULF) to induce STDP onto D1-MSNs in the direct pathway. The results described here are consistent with an emerging body of literature suggesting that reducing alcohol-associated D1-MSN hyperactivity or increasing D2-MSN hypoactivity reduces alcohol seeking and consumption 9,10,[22][23][24][25][26][27][28][29][30] . We tested the hypothesis that GPi/ACC ULF-STDP(+) will selectively decrease alcohol consumption and D1-MSN synaptic strength in a mouse model of AUD (Figure 7).…”

Section: Discussionsupporting

confidence: 88%

“…Chronic alcohol consumption has been shown to cause permanent hyperactivity of D1-MSNs and permanent hypoactivity of D2-MSNs in the DMS via maladaptive cortical glutamatergic signaling from areas such as the ACC 7,[19][20][21][22] . Studies have shown that reducing the ratio of DMS D1-MSN/D2-MSN signaling imbalance reduces pathological alcohol seeking behavior 9,10,[22][23][24][25][26][27][28][29][30] . Furthermore, a recent report demonstrated that inducing long-term depression (LTD) by applying a single 10-minute epoch of low frequency (1Hz) optogenetic stimulation of ACC projections to the DMS, combined with systemic D1-dopamine receptor antagonism, leads to a reduction in alcohol consumption lasting for nine days 28 .…”

Section: Introductionmentioning

confidence: 99%

Deep brain stimulation re-imagined: An ultra-low frequency spike timing dependent plasticity-based approach for treating alcohol use disorder

Asp

Boschen

Chang

et al. 2022

Preprint

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Alcohol use disorder (AUD) is a chronic relapsing brain disorder characterized by an impaired ability to stop or control alcohol consumption despite adverse social, occupational, or health consequences. AUD affects nearly one-third of adults at some point during their lives, with an associated cost of approximately $249 billion annually in the U.S. alone. The effects of alcohol consumption are expected to increase significantly during the COVID-19 pandemic, with alcohol sales increased by approximately 54%, potentially exacerbating health concerns and risk-taking behaviors. Unfortunately, existing pharmacological and behavioral therapies for AUD have historically been associated with poor success rates, with approximately 40% of individuals relapsing within three years of treatment. Pre-clinical studies have shown that chronic alcohol consumption leads to significant changes in synaptic function within the dorsal medial striatum (DMS), one of the brain regions associated with AUD and responsible for mediating goal-directed behavior. Specifically, chronic alcohol consumption has been associated with hyperactivity of dopamine receptor 1 (D1) medium spiny neurons (MSN) and hypoactivity of dopamine receptor 2 (D1) MSNs within the DMS. Optogenetic, chemogenetic, and transgenic approaches have demonstrated that reducing the D1/D2 MSN signaling imbalance decreases alcohol self-administration in rodent models of AUD. Here, we present an electrical stimulation approach that uses ultra-low (≤ 1Hz) frequency (ULF) spike-timing dependent plasticity (STDP) in mouse models of AUD to reduce DMS D1/D2 MSN signaling imbalances by stimulating D1-MSN afferents into the GPi and ACC glutamatergic projections to the DMS in a time-locked stimulation sequence. Our data suggest that GPi/ACC ULF-STDP selectively decreases DMS D1-MSN hyperactivity leading to reduced alcohol consumption without evoking undesired affective behaviors using electrical stimulation rather than approaches requiring genetic modification. This work represents a step towards fulfilling the unmet need for a reliable method of treating severe AUD through cell-type specific control with clinically available neuromodulation tools.

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“…AUD is made up of two critical behaviors: alcohol seeking and alcohol taking (Lüscher et al, 2020). Several studies have used optogenetic or chemogenetic techniques to study the behaviors underlying AUD (Hellard et al, 2019, Cheng and Wang, 2019, Cheng et al, 2021), but few have examined the interplay of neural substrates related to these distinct behaviors. However, there is evidence to believe that alcohol-seeking and -taking behaviors may involve distinct cellular substrates (Lüscher et al, 2020); for example, Renteria et al (2020) found no relationship between the degree of habitual EtOH seeking and escalated consumption.…”

Section: Introductionmentioning

confidence: 99%

Optogenetic inhibition of light-captured alcohol-taking striatal engrams facilitates extinction and suppresses reinstatement

Vierkant,

Xie,

Huang

et al. 2024

Preprint

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BackgroundAlcohol use disorder (AUD) is a complex condition, and it remains unclear which specific neuronal substrates mediate alcohol-seeking and -taking behaviors. Engram cells and their related ensembles, which encode learning and memory, may play a role in this process. We aimed to assess the precise neural substrates underlying alcohol-seeking and -taking behaviors and determine how they may affect one another.MethodsUsing FLiCRE (Fast Light and Calcium-Regulated Expression; a newly developed technique which permits the trapping of acutely activated neuronal ensembles) and operant-self administration (OSA), we tagged striatal neurons activated during alcohol-taking behaviors. We used FLiCRE to express an inhibitory halorhodopsin in alcohol-taking neurons, permitting loss-of-function manipulations.ResultsWe found that the inhibition of OSA-tagged alcohol-taking neurons decreased both alcohol-seeking and -taking behaviors in future OSA trials. In addition, optogenetic inhibition of these OSA-tagged alcohol-taking neurons during extinction training facilitated the extinction of alcohol-seeking behaviors. Furthermore, inhibition of these OSA-tagged alcohol-taking neurons suppressed the reinstatement of alcohol-seeking behaviors, but, interestingly, it did not significantly suppress alcohol-taking behaviors during reinstatement.ConclusionsOur findings suggest that alcohol-taking neurons are crucial for future alcohol-seeking behaviors during extinction and reinstatement. These results may help in the development of new therapeutic approaches to enhance extinction and suppress relapse in individuals with AUD.

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The use of chemogenetic approaches in alcohol use disorder research and treatment

Cited by 12 publications

References 69 publications

An ultra-low frequency spike timing dependent plasticity-based approach for treating alcohol use disorder

An ultra-low frequency spike timing dependent plasticity-based approach for treating alcohol use disorder

Deep brain stimulation re-imagined: An ultra-low frequency spike timing dependent plasticity-based approach for treating alcohol use disorder

Optogenetic inhibition of light-captured alcohol-taking striatal engrams facilitates extinction and suppresses reinstatement

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