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. Author manuscript; available in PMC: 2016 Jun 10.
Published in final edited form as: Physiol Behav. 2009 Dec 13;99(4):445–450. doi: 10.1016/j.physbeh.2009.12.005

Region-specific alteration in brain glutamate: Possible relationship to risk-taking behavior

Bernadette M Cortese a, Todd R Mitchell b, Matthew P Galloway c,d, Kristen E Prevost c, Jidong Fang e, Gregory J Moore e,f, Thomas W Uhde a,*
PMCID: PMC4902005  NIHMSID: NIHMS791769  PMID: 20006966

Abstract

Risk-taking behaviors involve increased motor activity and reduced anxiety in humans. Total sleep deprivation (SD) in animals produces a similar change in motor and fear behaviors. Investigators studied region-specific brain levels of glutamate in rats after TSD, an animal model of risk-taking behavior. We investigated the effects of sleep deprivation on these behaviors and associated levels of brain glutamate. Compared to the controls, the sleep-deprived rats spent a significantly greater percentage of time in the open arms of the elevated plus maze (EPM), demonstrating reduced fear-like and increased risk-taking behaviors. Additionally, sleep deprivation was associated with a significant increase in glutamate levels in the hippocampus and thalamus. An inverse relationship between glutamate in the medial prefrontal cortex and risk taking in the EPM and a positive association between the ratio of glutamate in the hippocampus to medial prefrontal cortex and risk taking was revealed. The role of sleep deprivation-induced changes in brain glutamate and its relationship to anxiety, fear, and posttraumatic stress disorder (PTSD) is discussed.

Keywords: Glutamate; Risk taking; Anxiety; Fear; Posttraumatic stress disorder (PTSD); Sleep deprivation; Rats; Elevated plus maze; Cortico-limbic circuit; Medial prefrontal cortex; Hippocampus; Amygdala; Thalamus; High resolution-magic angle spinning proton; magnetic resonance spectroscopy; (HR-MAS, 1H MRS)

1. Introduction

The brain glutamate system plays an important role in the neurobiology of animal fear and human anxiety. For example, in laboratory animals, the blockade of glutamate neurotransmission results in reduced fear behaviors in the elevated plus maze (EPM) and an attenuated stress-induced increase in acoustic startle [1–5]. Consistent with these data, drugs that attenuate glutamate activity in humans are efficacious in the treatment of anxiety [6–12].

Separate lines of investigation indicate that sleep deprivation, regardless of the sleep restriction methods utilized (i.e., sleep fragmentation, selective REM deprivation, or total sleep restriction), is associated with reduced fear behaviors in animal models of anxiety including the EPM [13,14], open field [15–17], and preference for novelty tests [18]. Given that glutamate blockade and sleep deprivation both reduce fear behaviors, one would expect sleep deprivation to decrease brain glutamate in selective brain regions. While sleep deprivation has been shown to increase glutamate levels in whole brain (i.e., cerebral cortex) [19], a seemingly apparent contradiction to the aforementioned effects of glutamatergic blockade on fear/anxiety, no research team has investigated region-specific levels of glutamate on fear and risk-taking behaviors.

Risk-taking behavior can be conceptualized as reduced fear and increased (i.e. impulsive) motor activity. Interestingly, sleep deprivation, in addition to its effects on fear behavior, has been shown to induce behavioral activation, increasing energy and motor activity, in both depressed humans and animal models [13,14,20–23]. Moreover, the behavioral phenotype displayed in animal models after sleep deprivation is similar to sleep deprivation-induced alterations in activity level, risk taking, decisionmaking, and constructive thinking skills demonstrated by humans [24–28].

The aim of the present study was to assess the behavioral and biochemical correlates of total sleep deprivation (TSD) in rats, with a focus on the relationship between a TSD-induced change in fear/risk-taking behavior, as measured by the EPM, and regional neurochemical concentrations of glutamate (Glu), as measured by high resolution, magic angle spinning proton magnetic resonance spectroscopy (HR-MAS, 1H MRS). We hypothesized that TSD-induced behavioral phenotypes (decreased fearfulness/increased risk taking) would be associated with regional changes in glutamate levels in the cortico-limbic (i.e., fear) circuit.

2. Materials and methods

2.1. Subjects

Thirty-two adult male Sprague–Dawley rats (70 days old) were housed individually in standard, solid bottom cages with ground corncob bedding and ad lib access to food and water. Animals were acclimated to a 23 °C holding room, on a 12 h light/12 h dark cycle, for at least 3 days prior to testing. All rats were handled in accordance with the Penn State College of Medicine Institutional Animal Care and Use Committee (PSCOM-IACUC) policy, which is in agreement with the NIH Guide for the Care and Use of Laboratory Animals.

2.2. Apparatus

The elevated plus maze (San Diego Instruments, San Diego, CA) was made of white plastic with lightly textured arms. The 2 open arms (50×10 cm) had a short 0.9 cm ledge, while the closed arms were the same size as the open but with 30.5 cm high walls. The 10 × 10 cm central square connected the opposite open and opposite closed arms, thus forming a plus-sign. The maze was elevated 30.5 cm above the floor and a video camera, mounted above the maze, was used to record activity that was later scored by technicians blinded to TSD treatment.

2.3. Procedure

2.3.1. Sleep deprivation

Sixteen rats were designated as experimental and were sleep deprived for 6h (N = 8) or 12h (N = 8) beginning at light onset (0700 hours). Total sleep deprivation (TSD) was performed by lightly tapping on cages and introducing novel objects to the animals, a method shown to stimulate exploratory behavior and prevent sleep [29]. Animals were watched continuously during TSD. Control animals (N = 16), located in a separate room, were permitted to sleep either 6 or 12h (N = 8 per group) during the same period. Testing for the 6 h-TSD and 6h-control groups was conducted between 1300 and 1400 hours and between 1900 and 2000 hours for the 12h-TSD animals and their respective controls. The 12 h light period was extended past 1900 hours on the day of testing to allow for the 1h needed to test all 12-hour animals. Animals were first tested in the EPM and then immediately sacrificed for neurochemical analysis following either TSD or sleep, depending on group assignment.

2.3.2. Elevated plus maze

Similar to the methods described by Pellow and colleagues, each rat was placed in the center of the maze facing a closed arm and allowed to freely explore for 5min [30]. The maze was cleaned with a 10% alcohol solution after each subject.

2.3.3. Brain tissue harvesting

Animals were decapitated, brains quickly removed and sliced to 2 mm coronal slices using a brain matrix (ASI, Warren, MI). Anatomically discrete punches (2.1 mm diameter) were obtained for each region of interest in the respective slice. All samples were immediately frozen on dry ice and stored at −80 °C until HR-MAS 1H MRS analysis. Punches were taken from brain regions of the cortico-limbic circuit that are considered important in the regulation of anxiety and fear and included the following: medial prefrontal (infralimbic) cortex (PFC), dorsal hippocampus (HPC), amygdala (AMYG), and medial thalamus (THAL).

2.3.4. HR-MAS 1H MRS

High resolution, magic angle spinning proton magnetic resonance spectroscopy (HR-MAS, 1H MRS), is an ex vivo imaging technique used to obtain rapid, high quality, quantitative, measurements of specific neurochemicals and metabolites in regionally defined samples of excised brain tissue [31–33]. An advantage of HR-MAS, 1H MRS, over traditional magnetic resonance spectroscopy (MRS), is higher signal-to-noise ratios and narrower line widths [34], allowing for more precise quantification of neurochemicals including glutamate. For additional details on HR-MAS, 1H MRS, please refer to our previous investigations [35–38].

Frozen intact tissue samples were weighed (~4 mg), then placed into a Bruker zirconium rotor (2.9 mm diameter, 10 µL capacity; Model 3542, Billerica MA) containing 4 µL of a 0.1 M phosphate-buffered solution (pH = 7.4), and 3-(trimethylsilyl)-1-propane sulfonic acid (1.5 mM, TMS; Sigma, St. Louis, MO). The rotor was then immediately placed into a Bruker 11.7T Avance 500 MR spectrometer where both the rotor and the sample were maintained at 4 °C, spun at a MAS rate of 4200 rpm, and positioned at the magic angle of 54.7° relative to the longitudinal magnetic field (B0). After a pre-saturation pulse for water suppression, tissue spectra were acquired with a Carr–Purcell–Meiboom–Gill (CPMG) rotor-synchronized pulse sequence (TR = 3500 ms, spectral bandwidth 8 kHz, 16 k complex points, 256 averages, total acquisition time of 15m38s) [33].

2.3.5. Data analysis

Elevated plus maze behavior was scored as follows: The amount of time spent in the closed arms and the number of entries into the closed arms were measured, as well as time in open arms and number of open entries. An entry into an open or closed arm was recorded if all 4 paws crossed into that arm. Total distance traveled was also measured using a pen and paper tracing method.

For neurochemistry, each HR-MAS 1H MRS spectrum was analyzed using the Linear Combination of Model Spectra software program (LCModel) [39]. Using calibration data from solutions with known concentrations, LCModel estimates both the neurochemical concentrations in the sample and the certainty of each concentration measurement (Cramer-Rao bounds). A custom basis set was generated with 28 calibrated phantoms of individual neurochemicals in buffer and conditions identical to those used for sample analysis. TMS resonates at 0.00 ppm and served as the external chemical shift reference. A customized model spectrum was developed in collaboration with Dr. S. Provencher to fit the tissue spectrum and calculate absolute neurochemical concentrations (nmol) with the Bruker 11.7T Avance MR system [39]. Although this method can reliably measure up to 28 neurochemicals and metabolites (Cramer-Rao bounds < 10%), we focused our hypothesis on glutamate (Glu), due to its implicated role in fear and anxiety. Absolute concentrations of MR visible neurochemicals were corrected for tissue weight and are expressed as nmol/mg of wet weight (mM).

Because there were no significant differences between the 6- and 12-hour TSD groups with respect to EPM behavior and neurochemistry, they were combined into a single group of total sleep-deprived rats (N = 16). Similar to TSD, the 6- and 12-hour control rats demonstrated no behavioral and neurochemical differences and were combined into one, non sleep-deprived, control group (N = 16). Raw data for the individual 6- and 12-hour groups will be provided to readers upon request. Behavioral data for all TSD and control subjects was available and included in the analyses. Neurochemical data was incomplete due to a lost tissue sample and unreliable quantification (Cramer-Rao bounds > 10%) for some samples. Missing neurochemical data were replaced with the conservative approach of a combined TSD and control group mean for the respective regional level of Glu. There was never more than 1 replaced datapoint for either the TSD or control group for any one region. Statistical analysis both with and without the replaced data revealed negligible changes in F and p values and did not change the overall outcome of significant findings reported below.

2.3.6. Statistics

Data analyses were performed using SPSS, Version 16.0 for Windows (SPSS, Inc., Chicago, IL). An overall effect of sleep deprivation on corticolimbic brain circuit chemistry and behavior was assessed with multivariate F tests for Glu and elevated plus maze variables (i.e. number of open arm entries, percentage of time spent in open arms, and total distance traveled). A significance level of p ≤ 0.05 was used to assess which dependent variables contributed to an overall effect. The relationship between glutamate levels in the brain and elevated plus maze behavior was assessed with Multiple Regression and Pearson's Correlational Analyses.

3. Results

Behavior: Sleep deprivation had a significant effect on EPM behavior (F2,29 = 12.11, p < 0.01) and was associated with both reduced fearfulness and increased motor activity. Specifically, the TSD group entered into and spent significantly more time in the open arms of the EPM than the non sleep-deprived control group (F1,31 = 9.89, p < 0.01; F1,31 = 11.03, p < 0.01, respectively; see Fig. 1a). Overall activity level, defined by total distance traveled, was also significantly increased in the TSD group compared to the controls (F1,31 = 25.05, p < 0.01; see Fig. 1b). Time spent in the open arms of the EPM and distance traveled were highly correlated (r = 0.78, p < 0.01). Covariate analysis revealed no effect of TSD on the number of entries and time spent in the open arms of the EPM once distance traveled was taken into account.

Fig. 1.

Fig. 1

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Elevated plus maze behavior after total sleep deprivation (TSD). The TSD group spent significantly more time in the open arms (a) and traveled a significantly greater distance (b) in the maze compared to the non-TSD group (* = p < 0.01).

Neurochemistry: Multivariate analysis revealed a significant main effect of sleep deprivation on glutamate levels in the cortico-limbic brain circuit (F4,27 = 2.82, p = 0.04). Within this circuit, TSD-induced regional increases in glutamate were also confirmed. Compared to the non sleep-deprived controls, the TSD group had a significantly greater amount of glutamate in the hippocampus (F1,31 = 4.22, p = 0.049) and medial thalamus (F1,31 = 9.09, p = 0.005; see Fig. 2).

Fig. 2.

Fig. 2

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Regional sleep deprivation-induced increases in glutamate. Glutamate was significantly increased in HPC and THAL in the total sleep deprivation (TSD) compared to the non-TSD rats (* = p ≤ 0.05, ** = p ≤ 0.01, HPC—Dorsal Hippocampus, THAL—Medial Thalamus, AMYG—Amygdala, and PFC—Medial Prefrontal Cortex).

The data were also analyzed by multiple regression to assess the relationship between sleep deprivation and regional glutamate levels (i.e., PFC, HPC, AMYG, and THAL) on risk-taking behavior in the EPM. Although the regression fit was modest (R2 = 41%), the overall relationship was significant (F5,31 = 3.62, p < 0.05). In addition to sleep deprivation (β = 0.54, t26 = 3.04, p < 0.01), glutamate levels in the medial prefrontal cortex significantly predicted the percentage of time that animals spent in the open arms of the EPM (β = −.32, t26 = −2.02, p ≤ 0.05). No other variables in the model, including glutamate levels in dorsal hippocampus, were significant (see Fig. 3a and b). Pearson's correlation analysis was also utilized in a secondary (exploratory) assessment of the relationship between risk-taking behavior and the ratio of limbic to prefrontal levels of glutamate. An initial analysis of the association between the ratio of glutamate in the dorsal hippocampus to glutamate in the medial prefrontal cortex and the percentage of time spent in the open arms of the maze revealed a positive relationship that reached a trend level of significance (r = 0.28, p = 0.13). This analysis, however, exposed an outlier in the ratio measurement of glutamate for one subject. In a subsequent analysis, we replaced the single outlier with a group mean value, revealing a significant positive relationship between the ratio of glutamate in the dorsal hippocampus to glutamate in the medial prefrontal cortex and the percentage of time spent in the open arms of the maze (r = 0.39, p < 0.05; see Fig. 3c).

Fig. 3.

Fig. 3

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a–c). Relationship between the concentration of regional glutamate and risk-taking behavior. There was a significant inverse relationship (r = −0.38, p < 0.05) between PFC glutamate and risk-taking behavior [i.e., percentage of time spent in the open arms of the EPM, (a)], no relationship between HPC glutamate and risk-taking behavior [r = 0.06, p = 0.74; (b)] and a positive relationship between the ratio of glutamate in dorsal hippocampus to glutamate in medial prefrontal cortical (HPC:PFC glutamate) and risk-taking behavior [r = 0.39, p < 0.05; (c)].

4. Discussion

The present study revealed a sleep deprivation-induced increase in time spent in the open arms of the elevated plus maze (EPM). Traditionally, an increase in open arm behavior in the EPM is thought to be an index of lowered fearfulness, as benzodiazepines are shown to reverse behavioral inhibition in this animal model of fear/anxiety [4]. More recently, the EPM has also been utilized as a measure of risk assessment and risk-taking behaviors in laboratory animals [40–42]. By classifying entry into and time spent in the open arms of the EPM as risky, our results demonstrate that sleep deprivation was associated with an increase in risk-taking behavior.

The association between sleep deprivation and risk taking is relevant to PTSD because traumatic events (e.g., military combat, motor vehicle accidents, etc.) often occur within the context of sleep restriction [43,44] and individuals with insomnia may be at increased risk for developing PTSD after traumatic experiences [45]. The manner in which sleep deprivation impacts that risk may include the degree to which one would engage in risk-taking behavior and/or situations that may increase the chances of experiencing a traumatic event. Our findings, that sleep deprivation is associated with risk-taking behavior in rats, are consistent with this notion.

In addition to its effect on risk taking, sleep deprivation was associated with an increase in motor activity exemplified by total distance traveled in the EPM. Increased motor activity following sleep deprivation has been reported previously in animal models [13,14,23], as well as depressed humans [20–22,46]. It is possible that the increase in open arm behavior is a byproduct of an increase in general activity/exploratory behavior. The EPM, however, provides a choice between entering the open versus closed arms, so that an animal is never forced to enter or spend any time in the open arms. Even though the TSD rats in the present study were significantly more active than the non-TSD rats, they were free to exclusively explore the closed arms for the duration of test. Despite this fact, they entered into and spent significantly more time in the open arms of the maze, behavior we therefore attribute to increased risk-taking. Clinical studies also show that sleep deprivation alters risk perception and behavior in motor [47], as well as non-motor [24,28] tasks. Extrapolating from the human studies of sleep deprivation-induced effects on non-motor tasks, it is likely that the increase in open arm behaviors is due to increased risk taking, as opposed to the effects of an exclusive increase in motor activity.

Although the sleep deprivation-induced behavioral changes in animal models have been shown to parallel the mood and motor activity effects demonstrated by humans, it is important to point out the methodological differences within both the preclinical and clinical sleep deprivation literature. What we know regarding the behavioral effects of sleep deprivation in humans is largely based on methods using shorter periods (e.g., one full night or second half of the night) of total sleep restriction [20–22,46,48], while the animal studies [14–18,23] have utilized a variety of sleep restriction methods, including prolonged periods of sleep deprivation (i.e., 12h to several days) and numerous sleep restriction techniques (i.e., sleep fragmentation, selective REM deprivation, or total sleep restriction). Although there are some data [49], much less is known about the effects of the shorter period of sleep deprivation, highlighting the importance of the present study. Surprisingly, we reported no significant differences in both EPM behavior and glutamate levels between the 6-hour and 12-hour TSD groups, suggesting that these behavioral and neurochemical changes take place after very short periods of sleep deprivation. This unexpected finding underscores the need to explore the effects of sleep deprivation over a broader range of sleep deprivation periods to better understand the onset and offset of effects. Additional studies utilizing a range of sleep deprivation periods, therefore are warranted to assess timing of effects on both behavior and neurochemistry.

A main goal of this investigation was to assess post sleep deprivation levels of HR-MAS, 1H MRS assessed glutamate, the most abundant excitatory neurotransmitter in the brain, and determine a potential relationship between sleep deprivation-induced changes in glutamate and behavior in the EPM. Our study revealed a sleep deprivation-induced effect on glutamate levels in the cortico-limbic brain circuit, with significant increases in the dorsal hippocampus and medial thalamus. Although HR-MAS, 1H MRS provides regional, absolute concentrations of glutamate, it cannot distinguish between intracellular and extracellular neurochemical levels and therefore, in the present study, does not inform us as to whether the increases in glutamate were due to increased glutamate neurotransmission and/or alterations in the large metabolic pool of glutamate. Interestingly, sleep deprivation-induced changes in NMDA current amplitude in hippocampal CA-1, in addition to sleep deprivation-induced impairments in long-term potentiation (LTP) and hippocampal-dependent learning and memory have all been well documented [50–53]. Both changes in NMDA-type glutamate receptor number and/or the change in the functional integrity of the NMDA receptors are likely mechanisms for the electrophysiological and behavioral changes demonstrated after sleep deprivation [54,55]. Although our method of sleep deprivation differed from many of these previous studies, our findings of increased MRS-measured glutamate in dorsal hippocampus is consistent with a compensatory response to a hypothetical sleep deprivation-induced loss of NMDA receptor number and/or function in this brain region.

As reviewed by Bannerman et al. [56], there is an abundance of data in support of the dorsal and ventral hippocampus as anatomically and functionally distinct subregions, with ventral hippocampus having a preferential role in emotion regulation (e.g., fear/anxiety) and dorsal hippocampus related to spatial learning and memory. With our hypotheses regarding the neurobehavioral effects of total sleep deprivation focused primarily on fear and anxiety (i.e., ventral hippocampus-dependent behaviors), glutamate levels in ventral hippocampus are both appropriate and important to assess. Unfortunately we did not obtain tissue samples from this particular subregion and, therefore, it is unknown whether sleep deprivation is associated with HR-MAS 1H MRS-measured glutamatergic changes in the ventral hippocampus.

An increase in glutamate has been previously reported after 12–24h of paradoxical sleep deprivation in rats [19] and 24-hours of total sleep deprivation in healthy adults [57], the present investigation to our knowledge, however, is the first to assess the relationship between sleep deprivation-induced changes in regional concentrations of glutamate and risk-taking behavior. Our results suggest that the lower the glutamate levels were in medial prefrontal cortex, the higher the percentage of time the animals spent in the open arms of the EPM. The inverse relationship between glutamate in this region and risk-taking behavior is noteworthy because of the strong evidence for the role of the medial prefrontal cortex in successful decision making under risk conditions [58–61]. Although our trend toward a SD-induced decrease in medial prefrontal glutamate was not statistically significant, the inverse relationship, taken together with other independent lines of evidence [62–64], suggests that glutamatergic mechanisms in this brain region may be modulating risk-taking behavior in the EPM. Although our finding suggests a possible role for medial prefrontal glutamate on risk-taking/fear behaviors, it is, of course, possible that other neurotransmitter systems and/or brain regions are important, or even critical, in the mediation of these behaviors.

We also reported a positive relationship between the ratio of glutamate in the dorsal hippocampus to medial prefrontal cortex (HPC: PFC) and risk-taking behavior in the EPM. Of interest, the main focus of most PTSD structural MRI investigation has been the prefrontal cortex and hippocampus, with many of these studies associating PTSD with anterior cingulate gray matter and hippocampal volume reductions [65–71]. Several independent laboratories have also demonstrated an exaggerated limbic (i.e., amygdala) and/or decreased medial prefrontal cortical response to aversive/traumatic stimuli in patients with PTSD [72–76].Within this context, it is interesting that we demonstrate TSD-induced changes in glutamate in the same brain regions that are consistently associated with PTSD. We speculate, therefore, that glutamatergic mechanisms may be important to risk-taking behaviors that, in humans, could lead to an increased likelihood of traumatic exposures. Future research needs to determine whether these sleep deprivation-induced glutamatergic changes are incidental, or whether they establish a chemical environment in fear-related neurocircuits (i.e. cortico-limbic) that is conducive to the development of PTSD.

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