Low‐dose alcohol: Interoceptive and molecular effects and the role of dentate gyrus in rats

Randall, Patrick A.; Lovelock, Dennis F.; Voorhies, Kalynn Van; Agan, Verda E.; Kash, Thomas L.; Besheer, Joyce

doi:10.1111/adb.12965

Cited by 9 publications

(7 citation statements)

References 63 publications

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“…As we were interested in necessity, we aimed for asymptotic inactivations with a 2mM muscimol dose. This is still considered moderate with respect to the broader literature, with 'high' being in the 5-8mM range (Katz et al, 2016;Randall et al, 2021). However, our pilot data suggest that higher doses do not increase effect sizes.…”

Section: Discussioncontrasting

confidence: 50%

Communication between the mediodorsal thalamus and prelimbic cortex regulates timing performance in rats

Cremers

et al. 2021

Preprint

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Predicting when future events will occur and adjusting behavior accordingly is critical to adaptive behavior. Despite this, little is known about the brain networks that encode time and how this ultimately impacts decision-making. One established finding is that the prefrontal cortex (PFC) and its non-human analogues (e.g., the rodent prelimbic cortex; PL) mediate timing. This provides a starting point for exploring the networks that support temporal processing by identifying areas that interact with the PFC during timing tasks. For example, substantial work has explored the role of frontostriatal circuits in timing. However, other areas are undoubtedly involved. The mediodorsal nucleus of the thalamus (MD) is an excellent candidate region. It shares dense, reciprocal connections with PFC-areas in both humans and non-human species and is implicated in cognition. However, causal data implicating MD-PFC interactions in cognition broadly is still sparse, and their role in timing specifically is currently unknown. To address this, we trained male rats on a time-based, decision-making task referred to as the 'peak-interval' procedure. During the task, presentation of a cue instructed the rats to respond after a specific interval of time elapsed (e.g., tone-8 seconds). We incorporated two cues; each requiring a response after a distinct time-interval (e.g., tone-8 seconds / light-16 seconds). We tested the effects of either reversibly inactivating the MD or PL individually or functionally disconnecting them on performance. All manipulations caused a comparable timing deficit. Specifically, responses showed little organization in time, as if primarily guided by motivational systems. These data expand our understanding of the networks that support timing and suggest that MD-PL interactions specifically are a core component. More broadly, our results suggest that timing tasks provide a reliable assay for characterizing the role of MD-PL interactions in cognition using rodents, which has been difficult to establish in the past.

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Section: Discussioncontrasting

confidence: 50%

Communication between the mediodorsal thalamus and prelimbic cortex regulates timing performance in rats

Cremers

et al. 2021

Preprint

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“…Low‐dose ethanol may affect different reward‐related circuits in males and females, which could contribute to the differences in ethanol effects observed here. Some differences in the neural circuit effects of low‐dose ethanol have been observed (Bryant et al., 2023; Cui & Koob, 2017; Randall et al., 2020), but this has yet to be thoroughly investigated in both male and female animals and as a result of chronic, as opposed to acute, exposure. Identifying the neurobiological substrates impacted by chronic low‐dose ethanol exposure may uncover new therapeutic targets to assist in preventing the development of inflexible behaviors that is associated with transition from casual drinking to AUD.…”

Section: Discussionmentioning

confidence: 99%

“…Only a small percentage of people who casually drink alcohol (~10%) go on to be diagnosed with or to develop an alcohol use disorder (AUD) (SAMHSA, 2021), but there is increasing evidence that exposure to even low doses of ethanol can impact the brain and behavior (Bryant et al., 2023; Cui & Koob, 2017; Randall et al., 2020). While it is known that chronic high‐dose ethanol exposure can promote the development of inflexible behaviors such as habits (Dickinson et al., 2002; O'Tousa & Grahame, 2014; Vandaele & Ahmed, 2021) that are hallmarks of AUD (McKim et al., 2016; Sjoerds et al., 2013), the consequences of lower doses of ethanol are less well‐characterized.…”

Section: Introductionmentioning

confidence: 99%

Sex and individual differences in the effect of chronic low‐dose ethanol on behavioral strategy selection

Bryant,

Singh,

Barker

2023

Alcohol: Clinical and Experimental Research

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BackgroundThe development of an alcohol use disorder (AUD) involves impaired behavioral control and flexibility. Behavioral inflexibility includes an inability to shift behavior in response to changes in behavioral outcomes. Low levels of ethanol drinking may promote the formation of inflexible, habitual reward seeking, but this may depend on the timing of ethanol exposure in relation to learning. The goal of this study was to determine whether a history of low‐dose ethanol exposure promoted contingency‐insensitive sucrose seeking and altered behavioral strategy selection.MethodsMale and female C57BL/6J mice were trained to perform a response (lever press) for sucrose on two different reinforcement schedules: one that is thought to promote inflexible responding (random interval) and one that maintains flexible responding (variable ratio [VR]). Following instrumental training each day, mice were exposed to saline or low‐dose ethanol (0.5 g/kg; i.p.) either proximal (1 h after) or distal (4 h after) to learning. Mice were then tested for sensitivity to changes in contingency in a contingency degradation test.ResultsA history of low‐dose ethanol exposure shifted behavioral strategy selection, as measured by reward tracking behavior, but this depended on sex and reinforcement schedule history. Both male and female mice used different strategies depending on the reinforcement schedule, but only males exhibited ethanol‐induced shifts in strategy selection. A history of low‐dose ethanol exposure did not impact contingency sensitivity in males but promoted insensitivity in females specifically on the VR lever.ConclusionsFemale mice show distinct behavioral effects of repeated, low‐dose ethanol exposure as compared to males, with sex differences in the use of reward tracking strategies to guide behavior. Future studies should investigate sex differences in the neural consequences of chronic low‐dose ethanol exposure that may underlie behavioral changes.

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“…Multiple brain regions known to be important for the encoding and updating of reward value information are impacted by chronic ethanol ( Lescaudron and Verna, 1985 ; DePoy et al, 2013 ; Barker et al, 2015 ; Trantham-Davidson et al, 2017 ; Ewin et al, 2019 ), and may be targets for the low dose ethanol effects observed here. In particular, the infralimbic prefrontal cortex, nucleus accumbens shell, and dentate gyrus have been shown to be activated as a result of low dose ethanol using c-Fos and Arc as markers of neuronal activity in rats, and this was not impacted by sex ( Randall et al, 2020 ). Additionally, it has been shown that brain-derived neurotrophic factor (BDNF) is increased in the hippocampus following low to moderate alcohol consumption ( Tizabi et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Reinforcement History Dependent Effects of Low Dose Ethanol on Reward Motivation in Male and Female Mice

Bryant

Singh

Barker

2022

Front. Behav. Neurosci.

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Alcohol use disorders (AUDs) are more prevalent in men than in women, though AUD diagnoses in women are growing rapidly, making an understanding of sex differences in alcohol-related behaviors increasingly important. The development of AUDs involves the transition from casual, low levels of alcohol drinking to higher, maladaptive levels. The ability of low dose alcohol to drive reward and drug seeking may differ in males and females, and this could underlie differences in susceptibility to AUD. In this study we sought to determine whether a history of chronic, low dose ethanol exposure (0.5 g/kg; i.p.) could drive sucrose reward seeking and motivation, and whether this differed between male and female mice. Adult mice were trained to lever press for a liquid sucrose reward on two reinforcement schedules: a random interval (RI) schedule and a variable ratio (VR) schedule. After training, mice were tested on each of these levers for reward motivation using a progressive ratio test. We found that a history of low dose ethanol exposure increased sucrose reward motivation in male mice, but only on the RI lever and only when exposure occurred proximal to learning. Female mice were more motivated for sucrose on the RI lever than the VR lever regardless of ethanol exposure condition. These findings indicate that training on different reinforcement schedules affects reward motivation. Further, we show that males are more susceptible to the effects of low dose ethanol on sucrose reward motivation than females. These data broaden our understanding of sex differences in reward seeking as a result of ethanol exposure.

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Low‐dose alcohol: Interoceptive and molecular effects and the role of dentate gyrus in rats

Cited by 9 publications

References 63 publications

Communication between the mediodorsal thalamus and prelimbic cortex regulates timing performance in rats

Communication between the mediodorsal thalamus and prelimbic cortex regulates timing performance in rats

Sex and individual differences in the effect of chronic low‐dose ethanol on behavioral strategy selection

Reinforcement History Dependent Effects of Low Dose Ethanol on Reward Motivation in Male and Female Mice

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