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Loss of day-night differences in VIP mRNA levels in the suprachiasmatic nucleus of aged rats
Neuroscience Letters 222 (1997) 99–102
Loss of day-night differences in VIP mRNA levels in the suprachiasmatic nucleus of aged rats Fumio Kawakami a ,*, Hitoshi Okamura b, Yoshitaka Tamada c, Yoshiro Maebayashi a, Kenji Fukui a, Yasuhiko Ibata c a
Department of Psychiatry, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602, Japan Department of Anatomy and Brain Science, Kobe University School of Medicine, Kusunoki-cho, Chuo-ku, Kobe 650, Japan c Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602, Japan b
Received 11 November 1996; revised version received 27 December 1996; accepted 27 December 1996
Abstract Age-related decreases in circadian oscillating activity are speculated to be one of the causes of psychiatric symptoms. To explore the effects of aging on vasoactive intestinal peptide (VIP) synthesis in the suprachiasmatic nucleus (SCN), we investigated the changes in VIP mRNA levels in aged rats compared with young-adult rats under a light/dark cycle using in situ hybridization combined with microcomputer-based imaging analysis. In the young-adult rats, total signals of VIP mRNA in the light-phase showed a significant decrease compared with those on the dark-phase. The VIP signal level in the aged rats was markedly lower than that in young-adults in both light and dark phases. Moreover, in the aged rats, there were no significant differences in VIP mRNA level between the light and dark phases. These results suggest that gene expression of VIP neurons, a main component of the circadian oscillating system, becomes disturbed in the aged rat brain. 1997 Elsevier Science Ireland Ltd. All rights reserved Keywords: Suprachiasmatic nucleus; Vasoactive intestinal peptide; Aging; In situ hybridization; Light/dark cycle
Age-related changes in biological rhythm are characterized by the following factors in man as well as experimental animals, (1) reductions in the amplitude of several circadian rhythms; (2) shortening of free running rhythm; (3) extension of the re-entrained time after changing light/ dark schedules; and (4) increased internal desynchronization [1,4,9,10]. The suprachiasmatic nucleus (SCN) is the highest center of circadian oscillation involved in a variety of behaviors and hormonal secretion [11,16]. The rat SCN is comprised of many peptidergic neurons showing characteristic distribution patterns [5]. Vasoactive intestinal peptide (VIP)containing neurons are the main component in the ventrolateral subdivision of the SCN, where many extrinsic inputs converge. Photic stimulus, the strongest external cue for entraining of neuronal activity to the light/dark (LD) cycle, reaches this part of the SCN directly through
* Corresponding author. Tel.: +81 75 2515612; fax: +81 75 2515839.
the retinohypothalamic tract and indirectly through the geniclohypothalamic tract [2,12]. VIP gene expression decreases in the day time and increases in the night time under the LD conditions [13,17]. This rhythmicity has been speculated to be evoked by photic stimulus since VIP levels are invariable in constant darkness and light exposure concomitantly decreases the level of VIP [17]. Evidence is accumulating that some aspects of the agerelated decay of circadian rhythm of behavior and hormonal rhythm are caused by dysfunction of circadian pacemaking activity of the SCN. Since VIP neurons in the SCN are speculated to play important roles in convening information regarding environmental illumination to the pacemaker and/or generation of circadian rhythm, we examined the effects of aging on daily VIP rhythm in the SCN. In the present study, we used an in situ hybridization technique combined with microcomputer-based imaging analysis and investigated the changes in level of VIP mRNA in aged rats compared with young-adult rats maintained under a 12 h LD cycle.
0304-3940/97/$17.00 1997 Elsevier Science Ireland Ltd. All rights reserved PII S0304-3940 (97 )1 3355-9
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F. Kawakami et al. / Neuroscience Letters 222 (1997) 99–102
Fig. 1. Hybridization signal of VIP mRNA in emulsion-coated sections in the SCN. Young-adult rats during the light phase (LY; (A)) and dark phase (DY; (B)). Aged rats during the light phase (LA; (C)) and dark phase (DA; (D)). Arrows indicate the third ventricle. oc, Optic chiasma. Bars, 100 mm.
Sixteen aged (24-month-old) male Wistar rats and 16 control young-adult (3-month-old) male rats were used in this study. They were housed under a 12 h light/dark schedule and given free access to food and water in a temperature-controlled (22–24°C) environment. In this study, Zeitgeber time 0 (ZT0; the time of the change from the dark-phase to light-phase) was 0600 h. Rats were divided into four groups according to the schedule described above; light-phase aged rats (LA), light-phase control young-adult (LY), dark-phase aged rats (DA) and darkphase control young-adult (DY). Animals were sacrificed for in situ hybridization at 1000 h (ZT4) in the light-phase or 2200 h (ZT16) in the dark-phase. Under deep pentobarbital anesthesia (Nembutal 60 mg/kg), animals were per-
fused with 4% paraformaldehyde in 0.1 M phosphate buffer (PB). After brains were postfixed in the same fixative solution for 6 h, serial frontal sections (60 mm thick) from the rostral to the caudal end of the SCN of each brain were cut on a cryostat. To minimize technical variation, SCN sections from one rat of each group (LA, LY, DA and DY) were gathered as one assemblage and processed simultaneously throughout the hybridization procedure. After deproteinization with proteinase K, the sections were re-fixed with 4% paraformaldehyde in 0.1 M phosphate-buffered saline (PBS). The 42-mer probe corresponding to part of the coding region of the rat VIP mRNA was synthesized with an automated DNA synthesizer [6,14], and was 3′ end-labeled using [35S]dATP (6000
F. Kawakami et al. / Neuroscience Letters 222 (1997) 99–102
Fig. 2. VIP mRNA signals shown as total amounts of photo-stimulated luminescence (PSL) on imaging plates. Data shown are means ± SD in LY, DY, LA and DA groups (n = 8 in each group). Statistical analysis was performed by Student’s t-test. (*P , 0.005).
Ci/mM; New England Nuclear) and terminal deoxynucleotidyl transferase (Takara, Japan). Hybridization using this probe was performed by a modification of the method described previously [13]. After hybridization, these sections were rinsed, dehydrated and air-dried. Hybridized sections were exposed to imaging plates (radiosensitive plates coated with BaFBr:Eu2+; Fuji Film) for 24 h, and the photo-stimulated luminescence (PSL) emitted from the imaging plate corresponding to the radioactivity of the sections was measured using an image analysis system (BAS 2000, Fuji Film Co.). The density of the PSL signal in the preoptic area of each section was used as a reference point. PSL values of the SCN in each rat were summed from the most rostral to the caudal end and averaged. After quantifying the signals, sections were dipped in Kodak NTB2 nuclear track emulsion (dilution 1:1 distilled water), exposed for 4 weeks and developed. Finally, tissue sections were counterstained with Cresyl violet. In emulsion-coated sections at both ages, the VIP mRNA signal was concentrated in the ventral portion of the SCN, and was absent in the dorsal portion. By visual inspection, there was a tendency for the intensity of VIP mRNA signal in cell bodies to be weaker in aged rats during both phases (LA and DA) than in young-adult controls (LY and DY) (Fig. 1). In young-adult controls, as reported previously [7,13], there was a difference in VIP mRNA signal intensity between the two phases, with weaker signals seen in the light-phase (LY) than in the dark-phase (DY) (Fig. 1A,B). However, in aged rats there were no changes between the light- (LA) and the dark-phases (DA) (Fig. 1C,D). Quantification of VIP mRNA level on the imaging plates demonstrated that the total PSLs of radioactivity in SCN from the aged rats regardless of the light-or dark-phase were markedly lower than those from the young-adults (Fig. 2). In the young-adult rats, the total PSLs of radioactivity in SCN in the light phase (LY;
101
174.5 ± 28.2, mean ± SD; n = 8) were significantly lower than those during the dark phase (DY; 198.1 ± 25.7, n = 8) (P , 0.005, Student’s t-test). However, in the aged rats, there was no significant difference in the VIP mRNA level between the light (LA; 125.1 ± 23.1, n = 8) and dark phase (DA; 123.6 ± 21.9, n = 8). The present results suggest that VIP gene expression in the SCN does not respond to the light/dark information in the aged brain. There are several explanations why the level of VIP mRNA in the SCN does not respond to the light/dark information in aged rats. Firstly, there is an agerelated reduction in the photic input signal to the SCN by the aged eye caused by cataracts, decreased photoreceptor activity and decreased activity of retinal ganglion cells. However, some decreases in input signal may not interfere with the circadian pacemaking system, since there were no differences in the re-entrained time after changing the light/dark conditions between rats with early onset cataract and young-adult controls [19]. Recent investigations using the mutant rd (retinal degeneration) mice indicated that rd mice are as capable of circadian responses to light stimulation as wild-type (+/+) controls [3,15]. Thus, it is difficult to surmise the lack of responsiveness of the VIP mRNA level in the SCN to light/dark information in aged rats is due solely to decreases in input signal with aging. It has been reported that there is a decreased response of the immediate early genes (IEGs) such as c-fos in the SCN of aged animals after photic stimulation [18]. Therefore, it is possible that the lack of response of the VIP mRNA level in the SCN to the light/dark information in aged rats is due to a decease in light-evoked intracellular signal transduction. The decrease in VIP mRNA level in aged rats at both phases of the LD cycle compared with young-adults may be due to the loss of VIP neurons in the SCN with aging, since neuronal loss was not rare in other brain areas in aged brain. However, it has been reported that there are no changes in the volume of the SCN, total cell number, mean somatic or nuclear volume in cells in aged rats, regardless of the presence of the age-related variations in circadian rhythms [8]. Therefore, the weakening of VIP mRNA signal in aged rats reflects the decline of VIP-production capacity of SCN VIP neurons rather than a reduction in the numbers of such cells. A recent report indicated that a significant decrease in the number of VIP expressing neurons in the SCN was found in female presenile Alzheimer’s disease patients [20]. The present result indicated that SCN cells decrease transmitter-synthesizing ability with age. If the decrease reflects the overall decrease of activity of VIP neurons, the main component of the circadian oscillating system in the SCN, the suspected age-related decrease of circadian oscillating activity in the SCN may be one of the etiological factors of several age-related psychiatric symptoms such as sleep disturbance and night delirium.
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F. Kawakami et al. / Neuroscience Letters 222 (1997) 99–102
This work was supported in part by grants from the Ministry of Education, Science and Culture, Japan. [1] Brock, M.A., Biological clocks and aging, J. Am. Geriat. Soc., 39 (1991) 74–91. [2] Card, J.P. and Moore, R.Y., Ventral lateral geniculate nucleus efferents to the rat suprachiasmatic nucleus exhibit avian pancreatic polypeptide-like immunoreactivity, J. Comp. Neurol., 206 (1982) 390–396. [3] Garcia´-Ferna´ndeaz, J.M., Jimenez, A.J. and Foster, R.G., The persistence of cone photoreceptors within the dorsal retina of aged retinally degenerated mice (rd/rd): implication for circadian organization, Neurosci. Lett., 187 (1995) 33–36. [4] Ingram, D.K., London, E.D. and Reynolds, M.A., Circadian rhythmicity and sleep: effects of aging in laboratory animals, Neurobiol. Aging, 3 (1982) 37–42. [5] Inouye, S.-I.T. and Shibata, S., Neurochemical organization of circadian rhythm in the suprachiasmatic nucleus, Neurosci. Res., 20 (1994) 109–130. [6] Kawakami, F., Okamura, H., Inatomi, T., Tamada, Y., Nakajima, T. and Ibata, Y., Serotonin depletion by p-chrolophenylalanine decreases VIP mRNA in the suprachiasmatic nucleus, Neurosci. Lett., 174 (1994) 81–84. [7] Kawakami, F., Okamura, H., Tamada, Y., Nakajima, T. and Ibata, Y., Changes in VIP mRNA levels in the rat suprachiasmatic nucleus following p-chlorophenylalanine (PCPA) treatment under the light-dark conditions, Neurosci. Lett., 200 (1995) 171–174. [8] Medeira, M.D., Sousa, N., Santer, R.M., Paula-Barbosa, M.M. and Gundersen, H.J.G., Age and sex do not affect the volume, cell numbers, or cell size of the suprachiasmatic nucleus of the rat: an unbiased stereological study, J. Comp. Neurol., 361 (1995) 585–601. [9] Miles, L.E. and Dement, W.C., Sleep and aging, Sleep, 3(1980) 119–120.
[10] Monk, T.H., Circadian rhythm – sleep disorders in elderly –, Clinics Geriat. Med., 5 (1989) 331–346. [11] Moore, R.Y., Organization and function of a central nervous system circadian oscillator in the suprachiasmatic hypothalamic nucleus, Fed. Proc., 42 (1983) 2783–2788. [12] Moore, R.Y. and Lenn, N.J., A retinohypothalamic projection in the rat, J. Comp. Neurol., 146 (1972) 1–14. [13] Okamoto, S., Okamura, H., Miyake, M., Takahashi, Y., Takagi, S., Akagi, Y., Fukui, K., Okamoto, H. and Ibata, Y., A diurnal variation of vasoactive intestinal peptide (VIP) mRNA under a daily light-dark cycle in the rat suprachiasmatic nucleus, Histochemistry, 95 (1991) 525–528. [14] Okamura, H., Kawakami, F., Tamada, Y., Geffard, M., Nishiwaki, T., Ibata, Y. and Inouye, S.-I.T., Circadian change of VIP mRNA in the rat suprachiasmatic nucleus following p-chrolophenylalanine (PCPA) treatment in constant darkness, Mol. Brain Res., 29 (1995) 358–364. [15] Provencio, I., Wong, S., Lederman, A.B., Argamaso, S.M. and Foster, R.G., Visual and circadian responses to light in aged retinally degenerate mice, Vision Res., 34 (1994) 1799–1806. [16] Rusak, B. and Zucker, I., Neural regulation of circadian rhythms, Physiol. Rev., 59 (1979) 449–526. [17] Shinohara, K., Tominaga, K., Isobe, Y. and Inouye, S.-I.T., Photic regulation of peptides located in the ventrolateral subdivision of the suprachiasmatic nucleus of the rat: daily variations of vasoactive intestinal polypeptide, gastrin releasing peptide and neuropeptide Y, J. Neurosci., 13 (1993) 793–800. [18] Sutin, E. L, Dement, W.C., Heller, H.C. and Kilduff, T.S., Lightinduced gene expression in the suprachiasmatic nucleus of young and aged rats, Neurobiol. Aging, 14 (1993) 441–446. [19] Yamaoka, S., Aging changes in circadian rhythm, Jpn. J. Clin. Psychiat., 24 (1995) 641–651. [20] Zhou, J.N., Hofman, M.A. and Swaab, D.F., VIP neurons in the human SCN in relation sex, age, and Alzheimer’s disease, Neurobiol. Aging, 16 (1995) 571–576.
Loss of day-night differences in VIP mRNA levels in the suprachiasmatic nucleus of aged rats Fumio Kawakami a ,*, Hitoshi Okamura b, Yoshitaka Tamada c, Yoshiro Maebayashi a, Kenji Fukui a, Yasuhiko Ibata c a
Department of Psychiatry, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602, Japan Department of Anatomy and Brain Science, Kobe University School of Medicine, Kusunoki-cho, Chuo-ku, Kobe 650, Japan c Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602, Japan b
Received 11 November 1996; revised version received 27 December 1996; accepted 27 December 1996
Abstract Age-related decreases in circadian oscillating activity are speculated to be one of the causes of psychiatric symptoms. To explore the effects of aging on vasoactive intestinal peptide (VIP) synthesis in the suprachiasmatic nucleus (SCN), we investigated the changes in VIP mRNA levels in aged rats compared with young-adult rats under a light/dark cycle using in situ hybridization combined with microcomputer-based imaging analysis. In the young-adult rats, total signals of VIP mRNA in the light-phase showed a significant decrease compared with those on the dark-phase. The VIP signal level in the aged rats was markedly lower than that in young-adults in both light and dark phases. Moreover, in the aged rats, there were no significant differences in VIP mRNA level between the light and dark phases. These results suggest that gene expression of VIP neurons, a main component of the circadian oscillating system, becomes disturbed in the aged rat brain. 1997 Elsevier Science Ireland Ltd. All rights reserved Keywords: Suprachiasmatic nucleus; Vasoactive intestinal peptide; Aging; In situ hybridization; Light/dark cycle
Age-related changes in biological rhythm are characterized by the following factors in man as well as experimental animals, (1) reductions in the amplitude of several circadian rhythms; (2) shortening of free running rhythm; (3) extension of the re-entrained time after changing light/ dark schedules; and (4) increased internal desynchronization [1,4,9,10]. The suprachiasmatic nucleus (SCN) is the highest center of circadian oscillation involved in a variety of behaviors and hormonal secretion [11,16]. The rat SCN is comprised of many peptidergic neurons showing characteristic distribution patterns [5]. Vasoactive intestinal peptide (VIP)containing neurons are the main component in the ventrolateral subdivision of the SCN, where many extrinsic inputs converge. Photic stimulus, the strongest external cue for entraining of neuronal activity to the light/dark (LD) cycle, reaches this part of the SCN directly through
* Corresponding author. Tel.: +81 75 2515612; fax: +81 75 2515839.
the retinohypothalamic tract and indirectly through the geniclohypothalamic tract [2,12]. VIP gene expression decreases in the day time and increases in the night time under the LD conditions [13,17]. This rhythmicity has been speculated to be evoked by photic stimulus since VIP levels are invariable in constant darkness and light exposure concomitantly decreases the level of VIP [17]. Evidence is accumulating that some aspects of the agerelated decay of circadian rhythm of behavior and hormonal rhythm are caused by dysfunction of circadian pacemaking activity of the SCN. Since VIP neurons in the SCN are speculated to play important roles in convening information regarding environmental illumination to the pacemaker and/or generation of circadian rhythm, we examined the effects of aging on daily VIP rhythm in the SCN. In the present study, we used an in situ hybridization technique combined with microcomputer-based imaging analysis and investigated the changes in level of VIP mRNA in aged rats compared with young-adult rats maintained under a 12 h LD cycle.
0304-3940/97/$17.00 1997 Elsevier Science Ireland Ltd. All rights reserved PII S0304-3940 (97 )1 3355-9
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F. Kawakami et al. / Neuroscience Letters 222 (1997) 99–102
Fig. 1. Hybridization signal of VIP mRNA in emulsion-coated sections in the SCN. Young-adult rats during the light phase (LY; (A)) and dark phase (DY; (B)). Aged rats during the light phase (LA; (C)) and dark phase (DA; (D)). Arrows indicate the third ventricle. oc, Optic chiasma. Bars, 100 mm.
Sixteen aged (24-month-old) male Wistar rats and 16 control young-adult (3-month-old) male rats were used in this study. They were housed under a 12 h light/dark schedule and given free access to food and water in a temperature-controlled (22–24°C) environment. In this study, Zeitgeber time 0 (ZT0; the time of the change from the dark-phase to light-phase) was 0600 h. Rats were divided into four groups according to the schedule described above; light-phase aged rats (LA), light-phase control young-adult (LY), dark-phase aged rats (DA) and darkphase control young-adult (DY). Animals were sacrificed for in situ hybridization at 1000 h (ZT4) in the light-phase or 2200 h (ZT16) in the dark-phase. Under deep pentobarbital anesthesia (Nembutal 60 mg/kg), animals were per-
fused with 4% paraformaldehyde in 0.1 M phosphate buffer (PB). After brains were postfixed in the same fixative solution for 6 h, serial frontal sections (60 mm thick) from the rostral to the caudal end of the SCN of each brain were cut on a cryostat. To minimize technical variation, SCN sections from one rat of each group (LA, LY, DA and DY) were gathered as one assemblage and processed simultaneously throughout the hybridization procedure. After deproteinization with proteinase K, the sections were re-fixed with 4% paraformaldehyde in 0.1 M phosphate-buffered saline (PBS). The 42-mer probe corresponding to part of the coding region of the rat VIP mRNA was synthesized with an automated DNA synthesizer [6,14], and was 3′ end-labeled using [35S]dATP (6000
F. Kawakami et al. / Neuroscience Letters 222 (1997) 99–102
Fig. 2. VIP mRNA signals shown as total amounts of photo-stimulated luminescence (PSL) on imaging plates. Data shown are means ± SD in LY, DY, LA and DA groups (n = 8 in each group). Statistical analysis was performed by Student’s t-test. (*P , 0.005).
Ci/mM; New England Nuclear) and terminal deoxynucleotidyl transferase (Takara, Japan). Hybridization using this probe was performed by a modification of the method described previously [13]. After hybridization, these sections were rinsed, dehydrated and air-dried. Hybridized sections were exposed to imaging plates (radiosensitive plates coated with BaFBr:Eu2+; Fuji Film) for 24 h, and the photo-stimulated luminescence (PSL) emitted from the imaging plate corresponding to the radioactivity of the sections was measured using an image analysis system (BAS 2000, Fuji Film Co.). The density of the PSL signal in the preoptic area of each section was used as a reference point. PSL values of the SCN in each rat were summed from the most rostral to the caudal end and averaged. After quantifying the signals, sections were dipped in Kodak NTB2 nuclear track emulsion (dilution 1:1 distilled water), exposed for 4 weeks and developed. Finally, tissue sections were counterstained with Cresyl violet. In emulsion-coated sections at both ages, the VIP mRNA signal was concentrated in the ventral portion of the SCN, and was absent in the dorsal portion. By visual inspection, there was a tendency for the intensity of VIP mRNA signal in cell bodies to be weaker in aged rats during both phases (LA and DA) than in young-adult controls (LY and DY) (Fig. 1). In young-adult controls, as reported previously [7,13], there was a difference in VIP mRNA signal intensity between the two phases, with weaker signals seen in the light-phase (LY) than in the dark-phase (DY) (Fig. 1A,B). However, in aged rats there were no changes between the light- (LA) and the dark-phases (DA) (Fig. 1C,D). Quantification of VIP mRNA level on the imaging plates demonstrated that the total PSLs of radioactivity in SCN from the aged rats regardless of the light-or dark-phase were markedly lower than those from the young-adults (Fig. 2). In the young-adult rats, the total PSLs of radioactivity in SCN in the light phase (LY;
101
174.5 ± 28.2, mean ± SD; n = 8) were significantly lower than those during the dark phase (DY; 198.1 ± 25.7, n = 8) (P , 0.005, Student’s t-test). However, in the aged rats, there was no significant difference in the VIP mRNA level between the light (LA; 125.1 ± 23.1, n = 8) and dark phase (DA; 123.6 ± 21.9, n = 8). The present results suggest that VIP gene expression in the SCN does not respond to the light/dark information in the aged brain. There are several explanations why the level of VIP mRNA in the SCN does not respond to the light/dark information in aged rats. Firstly, there is an agerelated reduction in the photic input signal to the SCN by the aged eye caused by cataracts, decreased photoreceptor activity and decreased activity of retinal ganglion cells. However, some decreases in input signal may not interfere with the circadian pacemaking system, since there were no differences in the re-entrained time after changing the light/dark conditions between rats with early onset cataract and young-adult controls [19]. Recent investigations using the mutant rd (retinal degeneration) mice indicated that rd mice are as capable of circadian responses to light stimulation as wild-type (+/+) controls [3,15]. Thus, it is difficult to surmise the lack of responsiveness of the VIP mRNA level in the SCN to light/dark information in aged rats is due solely to decreases in input signal with aging. It has been reported that there is a decreased response of the immediate early genes (IEGs) such as c-fos in the SCN of aged animals after photic stimulation [18]. Therefore, it is possible that the lack of response of the VIP mRNA level in the SCN to the light/dark information in aged rats is due to a decease in light-evoked intracellular signal transduction. The decrease in VIP mRNA level in aged rats at both phases of the LD cycle compared with young-adults may be due to the loss of VIP neurons in the SCN with aging, since neuronal loss was not rare in other brain areas in aged brain. However, it has been reported that there are no changes in the volume of the SCN, total cell number, mean somatic or nuclear volume in cells in aged rats, regardless of the presence of the age-related variations in circadian rhythms [8]. Therefore, the weakening of VIP mRNA signal in aged rats reflects the decline of VIP-production capacity of SCN VIP neurons rather than a reduction in the numbers of such cells. A recent report indicated that a significant decrease in the number of VIP expressing neurons in the SCN was found in female presenile Alzheimer’s disease patients [20]. The present result indicated that SCN cells decrease transmitter-synthesizing ability with age. If the decrease reflects the overall decrease of activity of VIP neurons, the main component of the circadian oscillating system in the SCN, the suspected age-related decrease of circadian oscillating activity in the SCN may be one of the etiological factors of several age-related psychiatric symptoms such as sleep disturbance and night delirium.
102
F. Kawakami et al. / Neuroscience Letters 222 (1997) 99–102
This work was supported in part by grants from the Ministry of Education, Science and Culture, Japan. [1] Brock, M.A., Biological clocks and aging, J. Am. Geriat. Soc., 39 (1991) 74–91. [2] Card, J.P. and Moore, R.Y., Ventral lateral geniculate nucleus efferents to the rat suprachiasmatic nucleus exhibit avian pancreatic polypeptide-like immunoreactivity, J. Comp. Neurol., 206 (1982) 390–396. [3] Garcia´-Ferna´ndeaz, J.M., Jimenez, A.J. and Foster, R.G., The persistence of cone photoreceptors within the dorsal retina of aged retinally degenerated mice (rd/rd): implication for circadian organization, Neurosci. Lett., 187 (1995) 33–36. [4] Ingram, D.K., London, E.D. and Reynolds, M.A., Circadian rhythmicity and sleep: effects of aging in laboratory animals, Neurobiol. Aging, 3 (1982) 37–42. [5] Inouye, S.-I.T. and Shibata, S., Neurochemical organization of circadian rhythm in the suprachiasmatic nucleus, Neurosci. Res., 20 (1994) 109–130. [6] Kawakami, F., Okamura, H., Inatomi, T., Tamada, Y., Nakajima, T. and Ibata, Y., Serotonin depletion by p-chrolophenylalanine decreases VIP mRNA in the suprachiasmatic nucleus, Neurosci. Lett., 174 (1994) 81–84. [7] Kawakami, F., Okamura, H., Tamada, Y., Nakajima, T. and Ibata, Y., Changes in VIP mRNA levels in the rat suprachiasmatic nucleus following p-chlorophenylalanine (PCPA) treatment under the light-dark conditions, Neurosci. Lett., 200 (1995) 171–174. [8] Medeira, M.D., Sousa, N., Santer, R.M., Paula-Barbosa, M.M. and Gundersen, H.J.G., Age and sex do not affect the volume, cell numbers, or cell size of the suprachiasmatic nucleus of the rat: an unbiased stereological study, J. Comp. Neurol., 361 (1995) 585–601. [9] Miles, L.E. and Dement, W.C., Sleep and aging, Sleep, 3(1980) 119–120.
[10] Monk, T.H., Circadian rhythm – sleep disorders in elderly –, Clinics Geriat. Med., 5 (1989) 331–346. [11] Moore, R.Y., Organization and function of a central nervous system circadian oscillator in the suprachiasmatic hypothalamic nucleus, Fed. Proc., 42 (1983) 2783–2788. [12] Moore, R.Y. and Lenn, N.J., A retinohypothalamic projection in the rat, J. Comp. Neurol., 146 (1972) 1–14. [13] Okamoto, S., Okamura, H., Miyake, M., Takahashi, Y., Takagi, S., Akagi, Y., Fukui, K., Okamoto, H. and Ibata, Y., A diurnal variation of vasoactive intestinal peptide (VIP) mRNA under a daily light-dark cycle in the rat suprachiasmatic nucleus, Histochemistry, 95 (1991) 525–528. [14] Okamura, H., Kawakami, F., Tamada, Y., Geffard, M., Nishiwaki, T., Ibata, Y. and Inouye, S.-I.T., Circadian change of VIP mRNA in the rat suprachiasmatic nucleus following p-chrolophenylalanine (PCPA) treatment in constant darkness, Mol. Brain Res., 29 (1995) 358–364. [15] Provencio, I., Wong, S., Lederman, A.B., Argamaso, S.M. and Foster, R.G., Visual and circadian responses to light in aged retinally degenerate mice, Vision Res., 34 (1994) 1799–1806. [16] Rusak, B. and Zucker, I., Neural regulation of circadian rhythms, Physiol. Rev., 59 (1979) 449–526. [17] Shinohara, K., Tominaga, K., Isobe, Y. and Inouye, S.-I.T., Photic regulation of peptides located in the ventrolateral subdivision of the suprachiasmatic nucleus of the rat: daily variations of vasoactive intestinal polypeptide, gastrin releasing peptide and neuropeptide Y, J. Neurosci., 13 (1993) 793–800. [18] Sutin, E. L, Dement, W.C., Heller, H.C. and Kilduff, T.S., Lightinduced gene expression in the suprachiasmatic nucleus of young and aged rats, Neurobiol. Aging, 14 (1993) 441–446. [19] Yamaoka, S., Aging changes in circadian rhythm, Jpn. J. Clin. Psychiat., 24 (1995) 641–651. [20] Zhou, J.N., Hofman, M.A. and Swaab, D.F., VIP neurons in the human SCN in relation sex, age, and Alzheimer’s disease, Neurobiol. Aging, 16 (1995) 571–576.