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/lp/springer-journals/cytomorphometric-changes-in-the-dorsal-raphe-neurons-after-rapid-eye-nRpG5NSsAa
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- Springer Journals
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- Copyright © 2010 by Ranjan et al; licensee BioMed Central Ltd.
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- Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
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- 1744-9081
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- 10.1186/1744-9081-6-62
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- 20964843
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Abstract
Objectives: This study was carried out to investigate the effect of rapid eye movement sleep (REMS) deprivation (REMSD) on the cytomorphology of the dorsal raphe (DR) neurons and to evaluate the possible role of REMSD- induced increased noradrenalin (NA) in mediating such effects. Methods: Rats were REMS deprived by the flowerpot method; free moving normal home cage rats, large platform and post REMS-deprived recovered rats were used as controls. Further, to evaluate if the effects were induced by NA, separate sets of experimental rats were treated (i.p.) with a1-adrenoceptor antagonist, prazosin (PRZ). Histomorphometric analysis of DR neurons in stained brain sections were performed in experimental and control rats; neurons in inferior colliculus (IC) served as anatomical control. Results: The mean size of DR neurons was larger in REMSD group compared to controls, whereas, neurons in the recovered group of rats did not significantly differ than those in the control animals. Further, mean cell size in the post-REMSD PRZ-treated animals was comparable to those in the control groups. IC neurons were not affected by REMSD. Conclusions: REMS loss has been reported to impair several physiological, behavioral and cellular processes. The mean size of the DR neurons was larger in the REMS deprived group of rats than those in the control groups; however, in the REMS deprived and prazosin treated rats the size was comparable to the normal rats. These results showed that REMSD induced increase in DR neuronal size was mediated by NA acting on a1-adrenoceptor. The findings suggest that the sizes of DR neurons are sensitive to REMSD, which if not compensated could lead to neurodegeneration and associated disorders including memory loss and Alzheimer’s disease. Background responsible for maintenance of ionic gradient across the Rapid eye movement sleep (REMS) is a unique but an cell membrane [10], and transmembrane potential of the essential physiological phenomenon expressed at least in neurons [11] have been studied systematically in relative higher-order mammals, including humans. REMS depri- detail. Changes in neuronal Na-K ATPase activity, cal- vation (REMSD) affects several psychosomatic illnesses cium concentration and structural proteins are likely to and prolonged deprivation may lead to death [1,2]. It affect neuronal morphology, integrity, functioning and also causes several biochemical and behavioral changes life span. In support, we have reported cytomorpho- [3,4]. At the cellular level REMSD has been reported to metric changes in noradrenalin (NA)-ergic, cholinergic affect intracellular calcium levels [5], membrane fluidity and GABA-ergic neurons in locus coeruleus (LC), ped- [6], expressions of various proteins including several unculopontine region and medial preoptic area of rats enzymes [3,7,8] and cytoskeletal proteins [7]. REMSD- after REMSD [12]. We have also observed evidence sug- induced changes in Na-K ATPase [9], which is primarily gesting increased apoptosis, disintegration of cytoskele- ton and loss of neurons in the above mentioned regions * Correspondence: remsbnm@yahoo.com in the rat brain after REMSD, which may have relevance School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, to REMS loss associated changes in higher integrated India processes and diseases e.g. Alzheimer’s disease [7,13,14]. Full list of author information is available at the end of the article © 2010 Ranjan et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ranjan et al. Behavioral and Brain Functions 2010, 6:62 Page 2 of 8 http://www.behavioralandbrainfunctions.com/content/6/1/62 NA is one of the key neurotransmitters involved in experiment, PRZ (2 mg/kg body wt, Sigma-Aldrich, REMS regulation [14]; its level in the brain reduces dur- St Louis, MO) was intraperitoneally (i.p.) injected once a ing REMS [15] and increases during REMSD [3,16]. The day to the rats during the last 4 days of REMSD; the NA-ergic neurons are predominantly concentrated in the dose was used based on our previous findings [12]. LC of rats [17] and these neurons are primarily responsi- At the end of experiment, the controls as well as ble for supplying most of the NA throughout the brain, experimental rats were anesthetized with ketamine-xyla- including the dorsal raphe (DR), the main site for seroto- zine (80 mg/kg and 32 mg/kg, respectively, i.p.; Chandra nergic neurons in the brain [18,19]. The DR neurons are Bhagat Pharma Pvt. Ltd, India). The brains were intra- reported to behave like the LC neurons, particularly in cardially perfused with 0.1 M phosphate buffer saline relation to REMS, which has been proposed to be due to (PBS) and 4% paraformaldehyde in 0.1 M phosphate the withdrawal (disfacilitation) of excitatory inputs from buffer (pH 7.4). The brains were fixed overnight in the the LC neurons [20]. The DR neurons continue firing same fixative and were cryoprotected in 30% sucrose in during REMS without atonia [21]. Further, since our pre- PBS. Thereafter, 40 μm frozen cryostat sections (Leica, vious studies have shown that REMSD-induced cytomor- Solms, Germany) through the antero-posterior extension phometric changes in neurons were induced by NA [12] of inferior colliculus (IC) and DR, as per the rat brain and that NA level increases in the brain after REMSD atlas of Paxinos and Watson [26], were collected in vials [16,22,23], we hypothesized that DR neurons also are containing PBS and were stored at 4°C for staining. likely to get affected by REMSD induced elevated levels Alternate sections through DR and IC were taken onto of NA. Alzheimer’s disease associated reduction in both gelatin-coated slides and were processed for Nissl stain- REMS as well as serotonin level [24,25] supports our ing. The sections on subbed slides were stained with 1% hypothesis. Therefore, in the present study, we evaluated cresyl violet and 0.1% thionin in acetate buffer following cytomorphology of DR neurons in experimental REMS- standard protocol of Nissl staining as reported earlier deprived rats and compared them with various control as [12]. The stained sections were dehydrated through well as PRZ-treated rats. We observed that after REMSD increasing concentration (30%, 50% and 70%) of ethanol the mean size of the DR neurons increased significantly for 5 minutes each while for 1 minute each in 90% and as compared to that of the control rats and that the 100% ethanol, cleared in xylene, cover slipped with dis- effects of REMSD were not observed in the PRZ-treated trene plasticizer xylene (DPX) and air dried before group, suggesting that the effect of REMSD were observing under microscope for cytomorphometric ana- mediated by NA. lysis. The slides were coded and analyzed by different researchers at random to minimize bias. Methods All the experiments were repeated in 4 sets and in Experiments were conducted on inbred male wistar rats each set there was one rat each of FMC, REMSD, LPC, (250–300 g) maintained in standard home cages under REC and PRZ-treated. The histochemically stained sec- 12/12 h light/dark cycle (lights on 7:30 AM) with ad tions were observed under Nikon E400 microscope libitum access to food and water. The experiments were (magnification 400X) and DR as well as IC was identi- approved by the Institutional Animal Ethics Committee fied anatomically as marked on the atlas (Figure 1) [26]. and every effort was made to minimize the number of The magnified views of neurons in these areas were cap- animals used and their sufferings. Free- moving control tured in a computer with the help of a charged coupled (FMC) rats were maintained in their normal dry home device (CCD) camera (JVC, Tokyo, Japan) fitted to the cages. Experimental rats were REMS deprived by the microscope by using dedicated software Image-Pro plus classical flowerpot method for 6 days because under 5.1.1 (Media Cybernetics, Silver Spring, MD). identical conditions REMSD for shorter period did not Only the neurons where nuclear boundaries were visi- significantly affect the cytomorphology of the LC and ble were selected for cyto-morphometric analysis. Bound- other neurons [12]. For REMSD, individual rats were aries of 30 to 50 neuronal perikarya from every third maintained on a 6.5-cm diameter platform surrounded serial section were traced on the computer screen (with by water. To rule out nonspecific effects, another group the help of a computer mouse) and their perimeters as of control rats was maintained on large (13-cm dia- well as areas were estimated by using cytomorphometric meter) platform (LPC) surrounded by water i.e. except analysis software (Image- Pro plus 5.1.1). Five to seven for larger-platform diameter, all other conditions such sections were studied from each animal and there remained identical to that of the experimental animals. were 4 animals per treatment group. Thus on an average A fourth recovery (REC) group of rats included those 900 ± 70 neurons were estimated from each anatomical animals which had been REMS deprived for 6 days and brain areas and each treatment group (FMC, LPC, were then allowed to live in normal cages for 3 days to REMSD, REC and PRZ). Further, another coworker ran- recover from lost REMS. In addition, in a separate set of domly reconfirmed the estimates in 3% to 5% of neurons. Ranjan et al. Behavioral and Brain Functions 2010, 6:62 Page 3 of 8 http://www.behavioralandbrainfunctions.com/content/6/1/62 Figure 1 Representative histological section through DR and IC (bregma -8.72 mm) on right half along with corresponding anatomical brain atlas (Paxinos and Watson, 1998) section on the left half are shown. The neurons in areas marked as DR and CIC, respectively, were studied. Abbreviations: DR, dorsal raphe; CnF, Cuniform nu; CIC, central nu of inferior colliculus; DTg, dorsal tegmental nucleus; ECIC, external cx of inferior collic; LDTg, laterodorsal tegmentum nu; LPAG, lateral periaqueductal gray; VTg, ventral tegmental nu. Intra-group analysis of variance (ANOVA) and nor- perimeter of each neuron and reasonably extrapolated mality tests on the data from all the animals of the possible changes in the size and shape of those neurons same group (FMC, LPC, REMSD, REC and PRZ) were caused by REMSD. The intra-group data from all the 4 conducted using Sigma Stat software (Jandel Scientific, animals within each of the 5 groups of rats were statisti- USA). Since the values were statistically comparable, the cally comparable; the p- values for DR neuronal area data from all the animals of the same group were pooled and perimeter in FMC, LPC, REMSD, REC and PRZ for further statistical analysis. The inter- group ANOVA groups were (0.38, 0.47, 0.43, 0.50 and 0.06) and (0.07, analysis between mean area and perimeter of the experi- 0.10, 0.11, 0.64 and 0.42), respectively. Data in each mental (REMSD) and each of the control groups (FMC, group also passed normality test (p > 0.2), suggesting LPC, REC and PRZ) were conducted using the same that the data followed a normal distribution and hence software. Similarly, data from within control groups data from different animals in the same group were were also compared using ANOVA. The mean area and pooled for further statistical inter- group ANOVA ana- mean perimeter were used to calculate the soma form lysis between mean area and perimeter of the experi- factor (FF) using the equation, FF = 4π (soma area/peri- mental (REMSD) and each of control groups (FMC, meter ) [27] to evaluate the changes in the shape of the LPC, REC, and PRZ). neurons. Cytomorphometric changes in the dorsal raphe neurons Results after various treatments Neurons occupy space in 3-Dimension (3-D); however, (1) Changes in the surface area in histological sections under microscope, we observe The mean (± SEM) surface area of Nissl-stained DR neu- them in 2-D space. Hence, in order to get the maximum rons in FMC was 122.13 ± 1.03 μm , which increased to information, we estimated the surface area as well as the 155.15 ± 1.38 μm after REMSD; an increase of 127.04% Ranjan et al. Behavioral and Brain Functions 2010, 6:62 Page 4 of 8 http://www.behavioralandbrainfunctions.com/content/6/1/62 and was statistically significant [F (1,7) = 367.69, p < This view may be supported by the fact that adjacent 0.001] as compared to FMC. The mean (± SEM) surface neurons in IC, where such REMS-related neurons have area in LPC, REC and PRZ groups of rats were 122.30 ± not been reported, remained unaffected. In our previous 2 2 2 0.98 μm , 123.19 ± 0.88 μm , 117.06 ± 0.80 μm ,which studies [12] rats were REMS deprived for 4, 6 and 10 were comparable to that of the FMC and among each days; significant changes were observed in the brain other. The mean surface area of the neurons was not areas including the LC after 6 and 10 days of REMSD, affected in control rats; however, the REMSD-induced whereas 4 days of REMSD was ineffective. To prevent increase in neuronal size was not observed in the REMS- unnecessary discomfort to the animals and to follow a deprived PRZ-treated (Figure 2 and Figure 3). uniform pattern of deprivation in this study also we (2) Changes in the perimeter used 6 days of REMSD paradigm. The mean (± SEM) perimeter of DR neurons increased To avoid estimating the same neuron more than once from 49.54 ± 0.22 μm in FMC to 55.64 ± 0.26 μmin we analyzed every third serial section. Since the sections REMSD; an increase of 112.31% [F (1,7) = 320.776, p < were 40 μ m thick it is unlikely that a neuronal soma 0.001] as compared to FMC. The mean perimeter of the would span three sections. Also, we selected neurons neurons in LPC, REC and PRZ treated rats was 48.91 ± where the nuclear boundaries were clearly visible. The 0.21 μm, 49.47 ± 0.19 μm and 48.15 ± 0.18 μm, respec- sampling error was minimized by counting a large num- tively and they were statistically comparable to that of ber of neurons (900 ± 70) at random across each of the FMC as well as among each other. Thus, although anatomical locations from 4 rat brains in each group. REMSD increased the neuronal perimeter as compared The intra-group data were not significantly different and to controls, the effect was not seen in REMS deprived hence the values were pooled for further analysis. rats treated with PRZ (Figure 2 and Figure 3). The flowerpot method [30] is reliable and it has been (3) No changes in the soma form factor reported that when continued beyond 24 hrs it deprives The mean FF (± SEM) values of neurons in FMC (0.61 animals maximally of REMS whereas non-REMS is least ± 0.02), LPC (0.64 ± 0.01), REMSD (0.62 ± 0.01), REC affected [31]; therefore, by far this is the best available (0.63 ± 0.01) and PRZ (0.63 ± 0.01) treated rats were method which has been extensively used globally for not significantly different. Since FF values were compar- experimental REMSD studies.Notwithstanding, like able, it indicated that REMSD-induced increase in the most other experimental procedures this method also area of the neuronal perikarya was proportional to the has some limitations, which are taken care of by using increase in square of perimeter of the neurons in various control groups. A common criticism of the use respective cases. of flowerpot method is that the animal may experience stress due to enforced immobilization and social isola- Cytomorphometric changes in the inferior colliculus tion. Our previous studies have shown that stress, if at neurons after various treatments all, induced by restricted movement or muscular over- The intra-group data from IC neurons also passed nor- activity, by either keeping them in restricted space or mality test (p > 0.2) and hence, they were pooled. The making the rats swim for various lengths of time, inter-group mean (± SEM) areas as well as perimeter (± respectively, were not the causes of flowerpot method SEM) of the IC neurons in FMC, LPC, REMSD, REC induced REMSD-associated increase in Na-K ATPase and PRZ-treated groups were not statistically different and chloride-sensitive Mg-ATPase activities [9,32]. In (Figure 2, Figure 3). The FF values were also statistically some studies multiple platforms have been used to comparable among all the five groups. avoid possible social isolation [33], however, in our stu- dies before the experiments, normally the rats were Discussion acclimatized for a few days by maintaining them indivi- In this study we observed that after REMSD the sizes of dually in cages; hence, isolation is unlikely to have influ- DR neurons increased in experimental rats as compared enced the results. We have conducted LPC to rule out to that of the control rats. The effects were specific to non-specific effects. In onestudy largeplatformrats REMSD and not non-specific effects because i) the neu- also showed elevated level of plasma corticosterone [33]. rons remained unaffected in LPC, where all other condi- However, in our studies since LPC rats did not show tions remained identical as those of the experimental significantly increased Na-K ATPase and chloride- sensi- group; ii) the REMSD induced changes in neuronal size tive Mg-ATPase activities [9,32] nor did they show sig- returned to the reference level (the FMC group) after nificant changes in neuronal sizes (neither earlier [12] recovery from REMSD (the REC group of rats); and iii) nor in this study), it may be safe to say that changes the affected neurons were located within the anatomical observed by us in the experimental rats are most likely region of the brain, the DR in this case, where func- due to REMSD. Notwithstanding, it is also important to tional REM-OFF neurons have been reported [28,29]. keep in mind that whichever method we use, in Ranjan et al. Behavioral and Brain Functions 2010, 6:62 Page 5 of 8 http://www.behavioralandbrainfunctions.com/content/6/1/62 Figure 2 Percentage changes in mean (± SEM) area and perimeter of neurons located in IC and DR in Nissl-stained sections under experimental (REMSD), treated (PRZ), and control (LPC and REC) conditions as compared to that of FMC taken as 100% are represented by histograms. Abbreviations are same as in the text, ***P < 0.001 significantly different from FMC. principle, experimental animals are subjected to a new treatment(s), as suffered by most cellulo-behavioral stu- environment, which by itself, may have some bearing on dies; hence, for confirmation one needs to study the the results [34]; designing suitable control experiment is same neuron before and after REMSD. always a challenge to the experimenter. We are also It was observed in this study that following REMSD, aware of the other limitation of this study e.g. the same the neurons in DR increased in size as compared to neuron could not be estimated before and after the controls; whereas neurons in IC were not affected. It Ranjan et al. Behavioral and Brain Functions 2010, 6:62 Page 6 of 8 http://www.behavioralandbrainfunctions.com/content/6/1/62 Figure 3 Representative photomicrographs of Nissl-stained sections under different experimental and control conditions are shown in this figure. Neurons in IC (upper panel; A, B, C, D and E) and DR (middle panel; F, G, H, I and J) are shown under different conditions. Magnified representative single cell in DR under different conditions are shown in (lower panel; K, L, M, N and O). All the photomicrographs from (upper and middle panels) are at 400X magnifications, whereas those of single neurons at (lower panel) are under 1000X magnification. Scale bars = 25 μm. Abbreviations are same as in the text. has been reported that REMSD alters membrane fluidity REMSD [37]. Since DR neurons apparently behave like [6], neuronal excitability [4,22], cytomorphometric REM-OFF neurons in relation to REMS, it is expected changes [12] and neuronal death [7]. The increased that those neurons might continue firing during excitability after REMSD is associated with increased REMSD. Tonic firing of neurons has been proposed to Na-K ATPase activity [9], which among other functions, build up a significant metabolic and/or ionic debt [35]. maintains the transmembrane potential and the osmotic Therefore, it is possible that upon REMSD an increased balance within cells to stabilize cell volume [12,35]. On activity in DR neurons will cause increased Na concen- the other hand, studies have shown correlation between tration inside the neurons. REMSD-induced increased neuronal size and neuronal excitability [35,36]. Although intracellular positivity, a reflection of depolarization of it might offer some explanation for observing increased neurons, supports this view [38]. Increased Na concen- neuronal size in the DR after REMSD, it does not tration and metabolites inside a cell would cause explain the possible mechanism of action and why IC increased water influx into the neurons due to osmosis, neurons were not affected by the REMSD. thus resulting in swelling and increased cell size [4,39]. There is evidence that suggests the presence of REM- However, recently it has been shown that a small frac- OFF type of cells in the DR nucleus [28] and those neu- tion of DR neurons may not behave as REM-OFF type rons do not cease firing during REMS without atonia [40] and the DR contains serotonergic as well as non- [21]. It has been reported that the LC possesses REM- serotonergic neurons [41]. Therefore, as a caution, it OFF as well as non-REM-OFF neurons and the former must be emphasized that all the DR neurons may not do not cease firing but instead continue firing during behave identically and such cellular and physiological Ranjan et al. Behavioral and Brain Functions 2010, 6:62 Page 7 of 8 http://www.behavioralandbrainfunctions.com/content/6/1/62 differences cannot be distinguished from the results of perimeter, whereas smoother surfaced DR neurons this study. swelled proportionately. Subject to experimental confir- We observed that a REMSD-induced increase in neu- mation we propose that DR neurons would be more ronal size was prevented by PRZ, suggesting that NA vulnerable to damage and lysis after REMSD than that acting on a1-adrenoceptor was responsible for REMSD- of LC neurons. induced increase in DR neuronal size. Although there is It has been reported that alterations in the size and no direct evidence to suggest that NA increases DR neu- shape of cells precede cellular degeneration [49]. It may ronal size, the following circumstantial evidences sup- be argued that neurons upon exposure to conditions port our contention; i) the LC NA-ergic neurons project detrimental to their survival try to compensate by alter- to DR neurons and regulate their activity [18]; ii) the ing sizes; however, in case of extreme insults, the com- activity of DR neurons is turned off by the withdrawal pensatory mechanism(s) fail and the neurons undergo of inputs from the LC during REMS [20]; iii) cessation degeneration. Our finding suggests that neurons in DR of firing of the LC- NA-ergic neurons is a necessity for increase in size after REMSD, which if not compensated occurrence and maintenance of REMS [42]; iv) the NA- could lead to neurodegeneration and contribute to ergic neurons in LC cease activity during REMS but are memory loss, tremors, aggression, depression, psychosis continuously active during REMSD [37]; v) the NA-syn- and possibly increase the risk for neurodegenerative thetic machinery are stimulated after REMSD [23]. conditions, such as Alzheimer’s disease. The findings of Therefore, it is likely that since after REMSD the NA this study may be relevant to at least Alzheimer’s disease level increases, it in turn modulates the DR neuronal because reduced levels of serotonin and imbalance size by acting on a1- adrenoceptors. Our contention between the serotonergic-cholinergic systems has been may be supported by the fact that REMSD did not affect reported in patients with Alzheimer’s disease [13] where the IC neurons, which do not possess a1- adrenoceptors REMS is also reduced [25]. These findings along with [43]. Our earlier findings that REMSD increased Na-K our previous results [7,12] show significant conse- ATPase activity [44,45] as well as size of LC-NA-ergic quences of REMSD on public health, especially for neurons [12] in the rat brain and both the effects were nightshift workers, viz. nurses, frequent fliers to various due to increased NA acting on a1- adrenoceptor further time zones, BPO employees, truck drivers and others support the findings of this study. However, it needs to such as students and elderly people in whom sleep is be investigated if the REMSD induced increased NA significantly compromised. would have differential effects on neurons releasing dif- ferent types of neurotransmitters because after REMSD Acknowledgements although the size of the NA-ergic neurons increased, the Funding from Department of Science and Technology and Department of size of cholinergic neurons showed a decrease [12]. Biotechnology are acknowledged. The soma FF of neurons was calculated as reported Author details earlier; neurons having FF value closer to 1 would be 1 School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, relatively rounder in shape than those closer to zero India. Current address: Behavioral Neuroscience Division, Dept. of Psychology, Arizona State University, Tempe, AZ 85287-1104, USA. [27]. It is interesting to note that, in DR, although both the neuronal area and perimeter increased after Authors’ contributions REMSD, the FF values remained unaltered. This may AR collected and analyzed the data as well as participated in preparing this MS; SB extended help while analyzing the data; BNM planned the study, happen only if the increase in area was proportional to arranged funds, trained co-workers and wrote the MS. All authors have read the increase in square of perimeter. Such a condition is and approved the final manuscript. most likely to take place in case of smooth and regular- Competing interests shaped neurons as compared to rough (undulated)-sur- The authors declare that they have no competing interests. faced neurons. This observation is in sharp contrast to the effect of REMSD on LC neurons, where the FF Received: 13 April 2010 Accepted: 21 October 2010 Published: 21 October 2010 values decreased [12]. 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Published: Oct 21, 2010