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. 2025 May 14;18(Suppl):100126. doi: 10.1016/j.nbscr.2025.100126

Effect of chronic sleep restriction on ethanol preference and cortical structural plasticity☆

Fernando Bravo-González a, Mario Eduardo Acosta-Hernández b, Hiram Tendilla-Beltrán c, Gonzalo Flores c, Fabio García-García b,⁎
PMCID: PMC12282829  PMID: 40703573

Abstract

Sleep loss is associated with a potential risk of using drugs such as cocaine, methamphetamines, and alcohol. Recently, our group showed that chronic sleep restriction (CSR) for 7 days/4 h induces a significant increase in ethanol intake and delta FosB immunoreactivity in the rat's prefrontal cortex. However, whether CSR promotes changes in structural plasticity that explain ethanol consumption is unknown. Therefore, the present study aimed to determine if CSR induces changes in the dendritic length, branching of the dendritic tree, and spine morphology of the pyramidal neurons from the prelimbic cortex and whether these structural changes are associated with ethanol consumption. For this purpose, adult male Wistar rats were divided into four experimental groups: control, CSR for 7 days/4 h daily, CSR + ethanol exposure, and ethanol exposure. The two-bottle free-choice paradigm was used to measure ethanol intake, and the gentle handling method was used for CSR. At the end of the experiment, the rats were euthanized, and their brains were dissected and processed by Golgi-Cox staining. Sholl analysis was used to characterize structural plasticity. Results show that CSR induced an increase in the ethanol index preference. In addition, ethanol intake and ethanol + CSR increased the total dendritic length, dendritic tree branching, and mushroom spines in prelimbic cortex neurons. In conclusion, changes in structural plasticity associated with CSR and continuous access to ethanol may translate into neuroadaptive changes that favor drug preference and subsequently reinforce addictive behavior.

Keywords: Neuronal plasticity, Sleep, Ethanol intake, Dendritic spines

Graphical abstract

Image 1

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Highlights

  • •

    • Seven-day sleep restriction increased ethanol preference in rats.

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    Ethanol plus sleep loss increased structural plasticity in PrL cortex without synergy.

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    Ethanol and sleep loss may drive abnormal plasticity linked to addiction.

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    Sleep restriction may promote vulnerability to addictive behaviors.

1. Introduction

Sleep is a fundamental biological process essential for maintaining physical and mental health. It plays a critical role in brain homeostasis, memory consolidation, synaptic plasticity, and the clearance of neurotoxic metabolites, such as beta-amyloid, through the glymphatic system (Baranwal et al., 2023; Frank et al., 2001; Xie et al., 2013). Additionally, sleep supports systemic physiological functions, including metabolic regulation, immune system activity, and cardiovascular health (Baranwal et al., 2023).

Insufficient sleep, whether due to chronic deprivation or poor sleep quality, has significant consequences. It is linked to cognitive impairment, emotional dysregulation, and an increased risk of developing neurodegenerative diseases, obesity, diabetes, and cardiovascular disorders (Irwin, 2015; Krause et al., 2017). Additionally, insufficient sleep is recognized as a risk factor for substance use and abuse. Sleep deprivation disrupts the regulation of the brain's reward system, particularly in the ventral striatum and prefrontal cortex. This disruption leads to heightened sensitivity to rewarding stimuli, including drugs and alcohol (Hasler et al., 2012).

Chronic sleep restriction (CSR) negatively affects decision-making and impulse control, making individuals more vulnerable to using substances as unhealthy coping mechanisms for stress or fatigue (Roehrs and Roth, 2001). Additionally, insufficient sleep can lead to changes in the hypothalamic-pituitary-adrenal axis, which can intensify cravings and compulsive behaviors related to substance use (Teicher et al., 2003). This bidirectional relationship between poor sleep and substance use highlights the necessity for interventions aimed at improving sleep health to help reduce the risk of addiction.

For instance, patients diagnosed with insomnia have a higher likelihood of alcohol consumption, while individuals in the abstinence phase of addiction often experience insomnia (Brower, 2003; Brower et al., 2001; Conroy et al., 2006; Currie et al., 2003). This connection between insomnia and alcohol consumption illustrates how CSR can contribute to the development of addictive behaviors.

Recent studies using rodent models have shown that disruptions in circadian rhythms, including CSR, can increase alcohol consumption. This increase is associated with a significant expression of delta FosB in the brain's reward circuit, potentially facilitating the development of addictive behaviors (García-García et al., 2021; Reséndiz-Flores and Escobar, 2019). In this sense, delta FosB is a transcription factor induced in the brain by chronic exposure to drugs of abuse, such as cocaine, heroin, and nicotine (Nestler et al., 2001). It belongs to the Fos family of transcription factors that regulate gene expression by binding to specific DNA sequences. For example, delta FosB regulated the expression of the CDK5, also known as cyclin-dependent kinase 5, which is a serine/threonine kinase that plays an essential role in dendritic length and spine formation (Chen et al., 2000; Cheung et al., 2007; Hawasli et al., 2007), two events related to structural plasticity.

Furthermore, insufficient sleep significantly affects structural plasticity in the cortex and hippocampus, which are crucial for cognitive and emotional regulation. Studies on rodent models have shown that sleep deprivation decreases dendritic spine density and alters spine morphology in the prefrontal cortex (PFC) (Acosta-Peña et al., 2015). Similarly, the hippocampus experiences synaptic remodeling, characterized by reduced dendritic complexity and spine density, particularly in CA1 pyramidal neurons that are vital for learning and memory processes (Acosta-Peña et al., 2015; Huang et al., 2022; Raven et al., 2019).

This study aims to test the hypothesis that CSR leads to changes in cortical structural plasticity that facilitate ethanol preference. Specifically, we investigate whether CSR affects dendritic length, branching of the dendritic tree, and spine morphology of pyramidal neurons in the prelimbic (PrL) cortex, and whether these structural changes are associated with an increased preference for ethanol.

2. Materials and methods

2.1. Animals

Adult male Wistar rats weighing 400–450 g were used (n = 20). The rats were housed at room temperature (21 ± 1.0 °C) under a 12:12 light-dark cycle. Lights turned on at 10:00 a.m. (ZT0). The animals had free access to water and food throughout the six weeks of treatment. Experimental procedures were approved and conducted according to the ethical committee (CICUAL, 2021-0018) in agreement with national (NOM-062-ZOO-1999) and international guidelines (Society for Neuroscience) for the production, care, and use of laboratory animals.

2.2. Two-bottle free-choice ethanol-drinking paradigm

Before initiating the ethanol consumption, the rats were acclimated to the experimental environment for one week. The rats in the ethanol-drinking groups were exposed to the two-bottle free-choice paradigm for six weeks (Hakami and Sari, 2017). Briefly, the rats had access to two bottles: one with an ethanol solution (15 % v/v) and the other with plain water. The position of the bottles was rotated daily to avoid position preference. During the first three weeks, the rats had access to ethanol or plain water to promote unconditioned ethanol consumption. Ethanol and water intake were assessed as basal intake in weeks 4–5. During week 6, identical measurements were taken. The ethanol and water consumption were measured at the end of the 24-h access period by weighing the bottles to obtain baseline intakes (g/day). The index preference of ethanol intake was calculated according to (mL ethanol solution intake)/(mL total fluid intake) ∗ 100 (Hakami and Sari, 2017).

2.3. Experimental groups

The rats were divided into two groups: a control group (n = 10 rats) and the CSR group (n = 10 rats). The control group was further divided into two subgroups: 1) Control group (Ctrl; n = 5), where rats were kept individually in their cage and had only access to two water bottles. 2) Ethanol group (EtOH; n = 5), where rats were kept individually in their cage and had access to one water bottle and one bottle containing an ethanol solution. The CSR group was also divided into two subgroups: 3) CSR group (n = 5) and EtOH + CSR group (n = 5). The rats were kept under the same conditions described in the previous groups, but in the sixth week of treatment, the rats were subjected to 4 h of sleep restriction per day for seven days (Fig. 1).

Fig. 1.

Fig. 1

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Diagram of the experimental design. Control group (Ctrl) rats without manipulation. Chronic sleep restriction group (CSR) rats with sleep restriction for 4 hours / 7 days using gentle handling method. Ethanol consumption group (EtOH) rats were exposed to ethanol using a two-bottle free-choice drinking paradigm. EtOH + CSR group rats were exposed to the ethanol and sleep-restricted in the sixth week. After meticulous manipulations, all rats were euthanized, and their brains were processed for Golgi-Cox staining. The structural plasticity was determined using the Sholl analysis.

2.4. Sleep restriction method

CSR was performed using the gentle handling method, which consisted in keeping the rats awake by gently touching their tail, back, or vibrissae with a soft-bristled brush when closed eyes, immobility, and stereotyped sleep posture were observed. CSR was carried out during the first 4 h of the light phase (ZT0-ZT4). A rotatory shift was scheduled to ensure that each researcher conducted sleep restriction for 2-h periods (2 shifts/4h). CSR was done in batches of four rats simultaneously, allowing researchers to monitor the rats’ behavior closely. Simultaneously, four Ctrl group rats remained in their cages in a separate room without manipulation. During the CSR period, water bottles were removed to avoid unintended dripping.

At the end of the treatments, the rats from each group were anesthetized one day after the last day of manipulation, that is, on day 8 at time ZT0. The rats received an intraperitoneal injection of sodium pentobarbital (120 mg/kg) and were perfused via the intracardiac route. Brains were dissected and processed with the Golgi-Cox impregnation technique. Total dendritic length and branching order were determined through Sholl analysis, as well as the density and categorization of dendritic spines (see Section 2.7).

2.5. Plasma corticosterone measurement

Plasma levels of corticosterone were measured to assess the physiological stress induced by CSR. Before perfusion, a sample (1 mL) of intracardiac blood was taken from each rat. Blood samples were collected in pre-cooled Eppendorf tubes containing EDTA as an anticoagulant. They were then centrifuged at 3000 rpm for 10 min, and the plasma was collected and stored at −80 °C for subsequent analysis of CORT levels using ELISA (Active Rat Corticosterone EIA, DSL-10-81100; Diagnostic System Laboratories Inc., Webster, Texas, USA).

2.6. Golgi-Cox staining

The staining was performed using the commercial kit FD Rapid Golgi Stain (FD Neurotechnologies). The brains were immersed in the impregnation solution composed of one part of solution A (potassium dichromate and mercuric chloride) and one part of solution B (potassium chromate) for 14 days in the dark. Then, the brains were transferred to solution C and stored for 72 h in the dark. Subsequently, coronal sections of 200 μm were obtained at the level of the PFC (Bregma 4.68–3.72 mm) (Paxinos and Watson, 2013) using a cryostat (Zeiss, Hyrax C25). The sections were collected, mounted on gelatin-coated slides, and processed with a mixture of 1 part solution D, 1 part solution E, and two parts Milli-Q water for 10 min. Then, the sections were rinsed twice with Milli-Q water and dehydrated in ethanol at 50 %, 75 %, 95 %, and 100 % (4 min per wash). Subsequently, they were cleared with xylene three times for 4 min each and finally coverslipped using Permount.

2.7. Sholl analysis

PrL layer III pyramidal neurons were selected for this study. Ten neurons per animal (10 neurons per animal, 200 neurons in total) were drawn using a lucid camera at 40× magnification by a trained person blind to treatment conditions. Golgi-Cox-stained pyramidal neurons were identified by their triangle-shaped soma, apical dendrites extending towards the pial surface, and numerous dendritic spines. The following criteria were used to select the drawn pyramidal neurons: (1) the location of the cell soma must be in layer III of the PrL and within half the thickness of the section; (2) complete impregnation of the neuron; (3) the presence of at least three basal dendrites that branched at least once; (4) a lack of evidence for changes in morphology attributed to Golgi-Cox staining. The basal dendrites of each pyramidal neuron, including all their ramifications, were quantified by Sholl analysis (Sholl, 1953) as follows. A transparent grid with concentric rings, equivalent to 10 μm spacing, was placed over the drawing, and the number of dendrites intersecting each ring was used to estimate the total dendritic length at 100× magnification.

Morphological analysis of dendritic spines was performed on the selected dendritic segments. Dendritic spine density was estimated by drawing at least 10 μm long segments from terminal tips of dendrites at 100× objective and a magnification changer (2×), allowing a magnification of 200×. Spines were classified based on observing the following morphological parameters: spine length, width, and length-to-width ratio. Spines were morphologically classified as thin, mushroom-like, stubby/wide, ramified, and unclassified (Bello-Medina et al., 2016; Brusco et al., 2010; Tendilla-Beltrán et al., 2019).

2.8. Statistical analysis

All data were expressed as mean ± S.E.M. Before performing the statistical analysis, the Shapiro-Wilk test was applied to verify the assumption of normality of the data. An unpaired t-test was used to compare ethanol consumption in the basal condition, in the sixth week, and the percentage of ethanol preferences between EtOH and EtOH + CSR groups.

The total dendritic length was analyzed using a generalized linear model (GLM) with a two-way repeated measures ANOVA design due to pseudoreplicates, which correspond to repeated measures at the day and week levels. When differences were observed, a Sidak post-hoc test was performed. A two-way repeated measures ANOVA was performed for dendritic length by branch order. The number of dendritic spine percentages was analyzed with a one-way ANOVA. For dendritic spine typification, a two-way repeated measures ANOVA was used. When differences existed, a Tukey post-hoc test was performed. Finally, for the analysis of CORT plasma levels, a Kruskal-Wallis test was used to determine statistical differences between groups. A p-value <0.05 was considered statistically significant. All statistical analyses were performed using GraphPad Prism 8.0.1 software.

3. Results

3.1. Alcohol intake

The comparative analysis between the basal ethanol intake versus sixth weeks did not show differences between both conditions [EtOH group, Basal: 3.57 ± 0.21 g/kg vs. W6: 3.19 ± 0.19 g/kg: t = 1.160, df = 19, p < 0.2603, Fig. 2A] or the EtOH + CSR group [Basal: 3.93 ± 0.20 g/kg vs. W6: 3.71 ± 0.26 g/kg: t = 0.6573, df = 19, p < 0.5188, Fig. 2B].

Fig. 2.

Fig. 2

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Basal values of the ethanol intake and effect of chronic sleep restriction (CSR). Panel A shows the mean basal values of ethanol intake during the fourth- and fifth weeks vs. the sixth week in the EtOH group. Panel B shows the mean basal values of ethanol intake during the fourth- and fifth weeks vs. the sixth week in the EtOH + CSR group. Panel C shows the ethanol intake in the sixth week, observing that CSR induces a slight increase in ethanol consumption. Panel D shows the ethanol intake mean induced by CSR. Panel E shows the increase in the ethanol preference percentage due to the influence of the day variable in the EtOH + CSR group. Panel F highlights the increase in the percentage preference for ethanol-induced by CSR. Panel G shows that water intake is reduced in the EtOH + CSR vs. EtOH group during the sixth week of the experimental protocol. The values show means ± S.E.M. ∗ p < 0.05, ∗∗p <0.009, ∗∗∗ p < 0.0001. Each experimental group n = 5.

Regarding the effect of CSR on ethanol consumption, CSR did not increase the average amount of ethanol consumed in the sixth week [EtOH: 3.19 ± 0.19 g/kg vs. EtOH + CSR: 3.71 ± 0.26 g/kg; t = 1.616, df = 12, p < 0.1321, Fig. 2D], without interaction between day and experimental group [F(6, 48) = 0.3112; p < 0.9281, Fig. 2C]. Interestingly, the ethanol preference percentage showed statistically significant differences influenced by the variable "day" [EtOH vs. EtOH + CSR, F (6, 24) = 4.58; p < 0.0031, Fig. 2E]. Sidak's post-hoc analysis revealed differences in the percentage between groups on day 2 (EtOH vs. EtOH + CSR, p < 0.0426). Additionally, the analysis also demonstrated that CSR rats had a higher preference for ethanol over water [EtOH: 17.34 ± 0.81 % vs. EtOH + CSR: 22.67 ± 1.54 %; t = 3.061, df = 12, p = 0.009, Fig. 2F].

3.2. Sholl analysis

3.2.1. Total dendritic length

As determined using the Sholl analysis, the total dendritic length of pyramidal neurons in the PrL cortex increased in the experimental groups compared to the Ctrl group. According to the two-way ANOVA, a significant effect of ethanol and CSR manipulation was observed [Ctrl: 365.20 ± 21.30 μm vs. CSR: 535.20 ± 24.88 μm vs. EtOH: 779.80 ± 20.39 μm vs. EtOH + CSR: 891.80 ± 14.19 μm; F (3, 16) = 133.7; p < 0.0001]. No differences were observed between neurons [F (9, 144) = 1.23; p = 0.3024], nor in the interaction between neurons and the experimental groups [F (27, 144) = 0.9947; p < 0.4801].

Furthermore, a multiple comparisons test using Tukey's post-hoc test indicated significant differences between the Ctrl group and each experimental condition: Ctrl vs. CSR, p < 0.0001; Ctrl vs. EtOH, p < 0.0001; Ctrl vs. EtOH + CSR, p < 0.0001. Moreover, significant differences were observed between the CSR and EtOH groups, p < 0.0001, and between the CSR and EtOH + CSR groups, p < 0.0001 (Fig. 3).

Fig. 3.

Fig. 3

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Ethanol (EtOH) intake and chronic sleep restriction (CSR) increase total dendritic length in the prelimbic cortex. Panel A represents the average value of total dendritic length in the four experimental groups. Panel B shows micrographs of representative cortical neurons (red arrows) in each experimental group. The values show means ± S.E.M. ∗p <0.0001, indicating a thorough data analysis and robust results.

3.2.2. Branch order analysis

In the PrL region, a two-way ANOVA revealed significant differences between experimental groups [F (3, 196) = 68.94; p < 0.0001] and branching order [F (7, 1372) = 246.3; p < 0.0001, Fig. 4]. Notably, a significant increase was observed in the first order in the CSR (p < 0.0249), EtOH (p < 0.0312), and EtOH + CRS (p < 0.0158) vs. Ctrl groups. In the second order, the EtOH (p < 0.0001) and EtOH + CSR (p < 0.0001) vs. Ctrl group were increased. Furthermore, analysis revealed significant differences between EtOH (p < 0.0033) and EtOH + CSR (p < 0.0001) vs. CSR group.

Fig. 4.

Fig. 4

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Chronic sleep restriction (CSR) and ethanol (EtOH) affect branching order in neurons from the prelimbic cortex. Panel A shows the branching order in each experimental group, observing that EtOH + CSR significantly increases the dendritic branching of the neurons. The values indicate means ± S.E.M. Statistical differences between groups are indicated by different letters above the bars. Bars that share the same letter are not significantly different, whereas bars with different letters indicate statistically significant differences between groups. The corresponding p-values are reported in Section 3.2.2 of the manuscript. Panel B shows drawings of reconstructed pyramidal neurons from four experimental groups. Colors represent different branching orders.

For the third order, significant increases were observed between CSR (p < 0.0116), EtOH (p < 0.0001), and EtOH + CSR (p < 0.0001) vs. Ctrl group. In addition, differences were found between EtOH (p < 0.0143) and EtOH + CSR (p < 0.0004) vs. CSR group. In the fourth order, significant increases were observed between CSR (p < 0.0303), EtOH (p < 0.0001), and EtOH + CSR (p < 0.0001) vs. Ctrl group. Additionally, statistically significant differences were found between EtOH (p < 0.0112) and EtOH + CSR (p < 0.0002) vs. CSR group, but not between EtOH vs. EtOH + CSR (p < 0.7576).

In the fifth order, an increase was observed in EtOH (p < 0.0161) and EtOH + CSR (p < 0.0011) vs. Ctrl groups. Also, differences were observed between EtOH + CSR vs. CSR groups (p < 0.0170). The sixth-order increase was found only between EtOH vs. Ctrl (p < 0.0186). No significant differences were found in the seventh and eighth branching orders between the experimental groups (Fig. 4).

3.2.3. Dendritic spine density

In our analysis of dendritic spine density, we quantified 160 neurons from the PrL cortex (PrL: Ctrl and CSR n = 5 each group; EtOH and EtOH + CSR n = 3 each group), with ten neurons per animal. In the PrL cortex, there were differences between the EtOH group and the Ctrl and CSR groups [Ctrl: 10.20 ± 0.46 spines vs. CSR: 10.03 ± 0.15 spines vs. EtOH: 11.65 ± 0.90 spines vs. EtOH + CSR: 11.81 ± 0.44 spines; F (3, 156) = 7.390; p < 0.001]. Post-hoc analysis using Tukey's test indicated significant differences between Ctrl vs. EtOH (p = 0.0174) and Ctrl vs. EtOH + CSR (p < 0.0065). We also found differences between the CSR and EtOH groups (p < 0.0060) and between CSR and EtOH + CSR (p < 0.0021) (Fig. 5A).

Fig. 5.

Fig. 5

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The total number and type of spines in neurons of the prelimbic cortex. Panel A underscores the role of ethanol (EtOH) intake and chronic sleep restriction (CSR) in increasing the total number of spines. No differences were observed between CSR compared to the control (Ctrl). The values show means ± S.E.M.∗p < 0.05; ∗∗p < 0.01. Panel B highlights that EtOH and EtOH + CSR increase the percentage of mushroom-type (M) dendritic spines. Interestingly, the percentage of the thin (T) and stubby (S) spines is reduced in EtOH and EtOH + CSR groups. Statistical differences between groups are indicated by different letters above the bars, p < 0.05. M=mushroom, T=thin, S=stubby, U=unclassified, and B=bifurcated.

3.2.4. Dendritic spine morphology

A two-way ANOVA revealed significant differences in spine morphology [F (4, 624) = 2519.01; p < 0.0001] and in the interaction between spine type and experimental group [F (12, 624) = 88.03; p < 0.0001], with no differences in the experimental condition [F (3, 156) = 1.457; p = 0.2285]. Tukey's post-hoc test indicated that mushroom-like dendritic spines increased in the EtOH and EtOH + CSR groups (p < 0.0001) (Fig. 5B).

In addition, multiple comparison tests revealed significant differences in the percentage of mushroom-like, thin, stubby, bifurcated, and unclassified spines among all the experimental groups (see Table 1 in the supplementary material).

3.3. Corticosterone plasma levels

The corticosterone plasma levels in each group were: Ctrl: 18.80 ± 1.73 ng/mL, CSR: 25.75 ± 1.98 ng/mL, EtOH: 24.68 ± 1.51 ng/mL, EtOH + CSR: 40.50 ± 5.48 ng/mL (Fig. 6). The mean rank values were Ctrl: 5.33, CSR: 12.67, EtOH: 12.08, EtOH + CSR: 19.92, and the Kruskal-Wallis test resulted in H (3, 23) = 13.08; p < 0.0045. Further multiple comparison testing showed that EtOH + CSR significantly increased corticosterone plasma levels vs. Ctrl group, p < 0.0018), while CSR and EtOH alone did not lead to a significant increase in corticosterone levels (Ctrl vs. CSR, p < 0.4157; Ctrl vs. EtOH, p < 0.5671, Fig. 6).

Fig. 6.

Fig. 6

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Serum corticosterone (CORT) levels in the experimental groups. Neither ethanol (EtOH) nor chronic sleep restriction (CSR) alone induced significant changes in serum CORT concentrations compared to the control (Ctrl) group. However, the combined EtOH + CSR treatment resulted in an increased in CORT levels. The values indicate means ± S.E.M. ∗p < 0.01.

4. Discussion

Several studies associate sleep restriction and a higher risk of drug consumption (Atrooz et al., 2022; De Nobrega et al., 2022; Deboer, 2018; García-García et al., 2021; Koob and Colrain, 2020; Lange and Wolf, 2023; Reeves-Darby et al., 2021; Roehrs et al., 1999; Sillaber and Henniger, 2004). Interestingly, CSR significantly reduced daily water intake in ethanol-exposed Wistar rats compared to non-restricted ethanol controls, suggesting a robust effect of sleep loss on hydration behavior. This reduction in water consumption aligns with previous findings showing that sleep deprivation can impair homeostatic fluid regulation (Everson and Szabo, 2011; Rezazadeh et al., 2025). In our study, the reduced water intake in the EtOH + RCS group occurred despite unchanged ethanol consumption. This indicates that the increase in ethanol preference percentage was primarily due to decreased water consumption and sensitizes the brain's reward system, making ethanol a more desirable stimulus than water. Further, basal ethanol consumption did not change during the five weeks before CSR, suggesting that the ethanol intake and preferences were the same in all rats in both experimental groups before CSR.

A limitation of our study is that sleep was not recorded after CSR. It is well documented that sleep restriction or deprivation induced a sleep rebound (Rechtschaffen et al., 1999; Tobler and Borbély, 1990). Total sleep time in NREM and REM is increased after sleep loss in rats and mice (Andersen et al., 2008; García-Garcí;a et al., 1998; Stephenson et al., 2015). Notably, 3 h of sleep deprivation during the rat's resting phase increases the total time of NREM sleep (Tobler and Borbély, 1990). For this reason, it is essential to consider that our CRS protocol may produce a NREM sleep rebound. Therefore, the time spent in NREM sleep following CSR may mitigate ethanol consumption without affecting the preference. However, this hypothesis needs to be tested. Some data indicate that REM sleep rebound decreased in alcohol drinking Long-Evans male rats immediately after seven days of the REM sleep deprivation (Aalto and Kiianmaa, 1984).

Regarding structural plasticity, CSR increased the total dendritic length in PrL pyramidal neurons, suggesting that sleep restriction alters structural plasticity. Dendrites conduct electrical activity from synapses to the neuron cell body or soma. Their structure and function are crucial for integrating synaptic inputs and determining the extent to which the neuron produces action potentials. An increase in the dendritic length may be interpreted as neuronal adaptations to form neuronal connections (Pascual-Leone et al., 2005; Spruston, 2008).

Interestingly, 5 h of sleep deprivation using the gentle handling method in Thy1-GFP M-line mice does not alter the dendritic length and spine density in the CA1 region of the hippocampus compared to non-restricted animals (Brodin et al., 2022). In contrast, another study found that 5 h of sleep deprivation in mice decreases dendritic spine numbers selectively in the hippocampal area CA1 (Havekes et al., 2016). Also, it is reported that 18 h of sleep deprivation over 21 days in Wistar rats decreases total dendritic length and dendritic spine density in the CA1 region (Noorafshan et al., 2018). However, significantly increased dendritic length and arborization in mPFC are reported in rats sleep-deprived for 24 h (Acosta-Peña et al., 2015). Due to contradictory results, it is essential to consider that the effects of sleep restriction or deprivation on structural plasticity depend on the duration and Zeitgeber time of the sleep deprivation method used. Also, it is necessary in future studies to analyze the structural plasticity effects induced by CRS in other brain regions such as the hippocampus or amygdala.

In summary, the results of the present study suggest that when sleep restriction is short but recurrent, it triggers cortical structural plasticity processes that could compensate for the adverse effects of sleep deprivation on brain integrity. In this sense, the role of the sleep rebound induced by recurrent sleep restriction is likely important. For example, 3 h of sleep rebound after 5 h of sleep deprivation in mice restored total dendritic length in hippocampal neurons compared to non-deprived mice (Havekes et al., 2016). Many lines of evidence have revealed the function of sleep in increasing, decreasing, or stabilizing synaptic strength and neuronal firing in various brain regions (de Vivo et al., 2017; Frank et al., 2001; Maret et al., 2011).

In this sense, sleep has been increasingly recognized as a dynamic process that supports neuroplasticity through local and global mechanisms of neural network modulation. According to Krueger and colleagues, sleep is not simply a passive state, but an active property emerging from localized neuronal assemblies (Krueger et al., 2008). These cell groups can independently alternate between sleep- and wake-like states, and their synchronization gives rise to whole-organism sleep. This model implies that structural plasticity at the synaptic level, such as synaptic strengthening and pruning, is closely tied to sleep processes, particularly within cortical microcircuits that undergo use-dependent changes (Krueger et al., 2008). These findings support the idea that sleep facilitates the stabilization and refinement of neural circuits, acting as a critical modulator of brain plasticity.

Regarding ethanol consumption, our data diverge from previous reports demonstrating that chronic ethanol exposure impairs structural plasticity. For instance, Lawson et al. (2022) and Valentino and Volkow (2020) report generalized neurotoxic effects of ethanol, including alterations in synaptic architecture across cortical and subcortical regions. Specifically, Amodeo et al. (2021) showed a reduction in dendritic spine density in the primary motor cortex, particularly of thin-type spines, following chronic intermittent ethanol vapor exposure during adolescence in rats.

In contrast, our findings suggest preserving dendritic spine density despite prolonged ethanol intake, which may reflect region-specific, developmental-stage-dependent, or exposure-pattern-dependent differences in ethanol's neurobiological impact. Notably, our experimental paradigm differed in both duration and modality of ethanol exposure: we used a voluntary two-bottle choice method over six weeks in adult rats, as opposed to forced vapor exposure in rats.

Nonetheless, other studies have results that support our findings. For example, in adolescent mice exposed to vaporized ethanol, the spine density in neurons from the mPFC was increased (Jury et al., 2017). In addition, adult mice exposed to chronic intermittent ethanol exposure also increased their spine density in the lateral orbitofrontal cortex after seven days of withdrawal (McGuier et al., 2015). Therefore, taken together, these results suggest that recurrent ethanol intake has a differential effect across the central nervous system, apparently reinforcing connectivity in the brain circuits of reward, favoring compulsive seeking and drug dependence.

A previous study found that CSR (4 h/7 days) increased delta FosB immunoreactivity in the PFC, Ventral Tegmental Area, and Nucleus Accumbens shell and core (García-García et al., 2021). Delta FosB is a protein that acts as a molecular switch for addiction and regulates the expression of genes related to neuronal plasticity processes (Dos Santos et al., 2018; Lazenka et al., 2014; Lobo et al., 2013; Nestler, 2001; Nestler et al., 2001). For example, Delta FosB induces the expression of Cdk5, a protein required for dendritic spine formation (Ferreras et al., 2017; Mita et al., 2016; Ruffle, 2014). Therefore, CSR could partially promote neuronal plasticity by activating the delta FosB/Cdk5 cascade. However, future studies are needed to determine the expression of both proteins in CSR rats.

Positive neuroplastic processes induced by adverse events are known as abnormal plasticity (Medina, 2011), which may favor neuroadaptive mechanisms (Dos Santos et al., 2018; Volkow et al., 2019). Notably, ethanol intake induces an increase in mushroom-spine type; these spines facilitate the formation of functional synaptic contacts (Bosch and Hayashi, 2012; Bourne and Harris, 2007; Harris et al., 1992; Hayashi and Majewska, 2005; Oray et al., 2006; Ziv and Smith, 1996). Therefore, the consumption of substances of abuse could facilitate anomalous plasticity processes, which result in the strengthening of brain circuits for the consolidation of addictive behavior.

Ethanol intake + CSR increased all structural plasticity parameters analyzed without showing a synergistic effect between ethanol and CSR. The current study is the first to report the combined effect of these variables on neuronal morphology. These structural plasticity changes could create a brain environment for developing and maintaining anomalous behaviors (Basavarajappa and Subbanna, 2023; Radley and Morrison, 2005).

Regarding the CORT measurement, rats from the CSR group did not show a significant increase in CORT plasma levels compared to the Ctrl group. These results are in line with previous studies, such as those that show that 6 or 24 h of sleep deprivation in rats using the gentle handling protocol did not increase CORT levels compared to the non-deprived rats (Kalinchuk et al., 2010; Melgarejo-Gutiérrez et al., 2013). However, in our experiment, blood samples were collected one day after the last day of manipulation, that is, on day 8 at time ZT0 for all experimental groups; this time point corresponds to the lowest of the circadian CORT rhythm in rodents (Butte et al., 1976). This sampling time represents a limitation of the study, as it does not capture potential fluctuations in corticosterone plasma levels over the 24h. We do not know if CORT plasma levels varied across the weeklong CSR protocol or through the 6 weeks of ethanol consumption. In addition, as it is well documented that after continuous exposure to harmful stimuli, the organisms show an adaptative response to physiological stress (Burchfield, 1979; Herman, 2013), evaluation of CORT levels at different time points is warranted. In addition, rats from the EtOH group did not show a significant increase in CORT plasma levels compared to the Ctrl. This finding is consistent with previous evidence indicating that prolonged ethanol intake can induce glucocorticoid resistance, potentially through altered expression of glucorticoid receptor isoforms (Alhaddad et al., 2020). Interestingly, rats subjected to EtOH + CSR exhibited elevated CORT plasma levels compared to the Ctrl group. This elevation likely reflects an amplified hypothalamic-pituitary-adrenal (HPA) axis activation due to the combination of sleep restriction and ethanol exposure. The increased CORT levels may have contributed to the observed enhancements in dendritic arborization within the prelimbic cortex. While chronic stress and elevated glucocorticoids are often associated with dendritic retraction, some studies suggest that certain stress paradigms or glucocorticoid exposures can lead to region-specific dendritic growth, potentially as an adaptive response to stress (Anderson et al., 2016). For instance, Cook and Wellman (2004) reported that chronic stress can induce dendritic remodeling in the medial prefrontal cortex, highlighting the complexity of stress-induced neural plasticity. Therefore, the concurrent increase in CORT and dendritic arborization in the EtOH + CSR group may represent a unique neuroadaptive mechanism in response to compounded stressors.

5. Conclusions

While the effects of alcohol intake and sleep restriction on dendritic structure have been studied independently, research examining their combined impact, particularly in the PFC, is scarce. Future studies must clarify how these two factors influence synaptic remodeling and neurobehavioral outcomes. In conclusion, the study results show that ethanol consumption and CSR promote structural plasticity in the PrL cortex; these morphological changes may strengthen the brain circuit involved in addictive behavior through a phenomenon of anomalous plasticity.

Funding

This work was partially supported by CONAHCYT grant 254264 to F.G.G and a scholarship from CONAHCYT (742333) to F.B.G and H.T.B "Estancias posdoctorales por México" program.

Financial interest

The authors have no relevant financial or non-financial interest to disclose.

CRediT authorship contribution statement

Fernando Bravo-González: Writing – original draft, Methodology, Formal analysis, Data curation. Mario Eduardo Acosta-Hernández: Writing – original draft, Methodology, Formal analysis, Data curation. Hiram Tendilla-Beltrán: Formal analysis, Data curation. Gonzalo Flores: Writing – review & editing, Writing – original draft. Fabio García-García: Writing – review & editing, Writing – original draft, Supervision, Funding acquisition, Conceptualization.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Fabio Garcia-Garcia reports financial support was provided by CONAHCYT-Mexico. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgment

Thank you to Prof. James M. Krueger for the valuable comments and for reviewing the manuscript.

Footnotes

☆

This article is part of a special issue entitled: Festschrift in honor of JM Krueger's research.

Appendix A

Supplementary data to this article can be found online at https://doi.org/10.1016/j.nbscr.2025.100126.

Contributor Information

Fernando Bravo-González, Email: zs21000554@estudiantes.uv.mx.

Mario Eduardo Acosta-Hernández, Email: mariacosta@uv.mx.

Hiram Tendilla-Beltrán, Email: hiramtb20@gmail.com.

Gonzalo Flores, Email: gonzalo.flores@correo.buap.mx.

Fabio García-García, Email: fgarcia@uv.mx.

Appendix A. Supplementary data

The following is the Supplementary data to this article:

Multimedia component 1
mmc1.docx (18KB, docx)

Data availability

Data will be made available on request.

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