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The Role of the Intergeniculate Leaflet in Entrainment of Circadian

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The Role of the Intergeniculate Leaflet in Entrainment of Circadian The Journal of Neuroscience, January 1, 1999, 19(1):372–380 The Role of the Intergeniculate Leaflet in Entrainment of Circadian Rhythms to a Skeleton Photoperiod Kim Edelstein and Shimon Amir Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montreal, Quebec, Canada H3G 1M8 Mammalian circadian rhythms are synchronized to environmen- by 12 hr of darkness, but exhibited free-running rhythms when tal light/dark (LD) cycles via daily phase resetting of the circa- housed under an SPP consisting of two 1 hr light pulses given dian clock in the suprachiasmatic nucleus (SCN). Photic infor- at times corresponding to dusk and dawn. Despite IGL lesions mation is transmitted to the SCN directly from the retina via the and other damage to the visual system, the SCN displayed retinohypothalamic tract (RHT) and indirectly from the retinore- normal sensitivity to the entraining light, as assessed by light- cipient intergeniculate leaflet (IGL) via the geniculohypotha- induced Fos immunoreactivity. In addition, all IGL-lesioned, lamic tract (GHT). The RHT is thought to be both necessary and free-running rats showed masking of the body temperature sufficient for photic entrainment to standard laboratory light/ rhythm during the SPP light pulses. These results show that the dark cycles. An obligatory role for the IGL–GHT in photic en- integrity of the IGL is necessary for entrainment of circadian trainment has not been demonstrated. Here we show that the rhythms to a lighting schedule like that experienced by noctur- IGL is necessary for entrainment of circadian rhythms to a nal rodents in the natural environment. skeleton photoperiod (SPP), an ecologically relevant lighting schedule congruous with light sampling behavior in nocturnal Key words: suprachiasmatic nucleus; neuropeptide Y; imme- rodents. Rats with bilateral electrolytic IGL lesions entrained diate early gene; geniculohypothalamic tract; retinohypotha- normally to lighting cycles consisting of 12 hr of light followed lamic tract; body temperature Environmental light is necessary for stable entrainment of mam- light housing in hamsters (Pickard et al., 1987; Harrington and malian circadian rhythms, providing the critical cue for daily Rusak, 1988; Harrington, 1997) but not mice (Pickard, 1994) or resetting of the circadian clock in the suprachiasmatic nucleus of rats (Edelstein and Amir, 1999). IGL lesions, however, do not the hypothalamus (SCN) (Pittendrigh and Daan, 1976; Moore, prevent entrainment to standard laboratory LD cycles (Pickard et 1983; Morin, 1994; Roenneberg and Foster, 1997). Light pre- al., 1987; Harrington and Rusak, 1988; Johnson et al., 1989; sented near dusk delays the phase of the clock, whereas light Moore and Card, 1994; Harrington, 1997; Edelstein and Amir, presented near dawn advances the phase of the clock (Daan and 1999), suggesting only a minor contribution of the GHT to the Pittendrigh, 1976; Roenneberg and Foster, 1997). Photic infor- photic entrainment process. There is evidence, however, that IGL mation is transmitted to the SCN via two principal pathways: a lesions alter the phase angle of entrainment under a sinuosoidal direct retinal projection, the retinohypothalamic tract (RHT), lighting schedule (Pickard, 1989), consistent with Pickard’s idea and an indirect projection originating in the retinorecipient in- (Pickard et al., 1987) that the IGL is involved in photic entrain- tergeniculate leaflet (IGL), the geniculohypothalamic tract ment under natural lighting conditions. (GHT) (Card and Moore, 1991; Moore and Card, 1994; Morin, A possible role for the IGL in light-induced resetting of the 1994; Harrington, 1997). The RHT is thought to be both neces- circadian clock is further supported by recent evidence demon- sary and sufficient for photic entrainment. Disruption of the strating that neuropeptide Y (NPY), a neurotransmitter used by RHT, but not other retinofugal projections, prevents photic en- the GHT (Moore and Card, 1994; Harrington, 1997), exhibits a trainment to standard laboratory light/dark (LD) cycles (Dark diurnal rhythm in the SCN with peaks occurring at the time of and Asdourian, 1975; Pickard et al., 1987; Harrington and Rusak, light/dark transitions at dawn and dusk (Shinohara et al., 1993). 1988; Johnson et al., 1988, 1989). In contrast, a role for the NPY has been found to depress excitatory neurotransmission in IGL–GHT in the circadian response to light has not been well the SCN (van den Pol et al., 1996) and to block glutamate- established. Current evidence suggests that the IGL modulates induced phase shifts in SCN neuronal activity in vitro (Biello et the rate of re-entrainment to shifted LD cycles (Johnson et al., al., 1997) and light-induced phase advances in vivo (Weber and 1989; Harrington, 1997) and the circadian period during constant Rea, 1997). These findings raise the possibility that the IGL is involved in synchronization of circadian rhythms to discrete light Received Sept. 8, 1998; revised Oct. 2, 1998; accepted Oct. 12, 1998. pulses. This work was supported by grants from the Medical Research Council of Circadian rhythms of nocturnal animals can be entrained by Canada, the Natural Sciences and Engineering Research Council of Canada, and the Fonds pour la Formation de Chercheurs et l’Aide` a la Recherche (Que´bec). We brief, discrete pulses of light given at dusk and dawn (Pittendrigh thank Jane Stewart for helpful comments on this manuscript. and Daan, 1976; Rosenwasser et al., 1983; Stephan, 1983; De- Correspondence should be addressed to Shimon Amir, Center for Studies in Coursey, 1986). Housing under such a skeleton photoperiod Behavioral Neurobiology, Department of Psychology, Concordia University, 1455 de Maisonneuve Boulevard West H-1013, Montreal, Quebec, Canada H3G 1M8. (SPP) provides an ecologically relevant lighting schedule congru- Copyright © 1998 Society for Neuroscience 0270-6474/98/190372-09$05.00/0 ous with light-sampling behavior in nocturnal rodents under nat- Edelstein and Amir • IGL Lesion and Skeleton Photoperiod Entrainment J. Neurosci., January 1, 1999, 19(1):372–380 373 ural and simulated laboratory conditions (DeCoursey, 1986). Preparation of tissue. Animals were deeply anesthetized with sodium Moreover, inasmuch as exposure to light can suppress overt pentobarbital and perfused transcardially with 300 ml of cold physiolog- expression of some rhythmic variables (Mrosovsky, 1994), SPP ical saline (0.9% NaCl) followed by 300 ml of cold 4% paraformaldehyde in a 0.1 M phosphate buffer, pH 7.3. Brains were removed and post-fixed housing allows for the study of pacemaker entrainment in the overnight in 4% paraformaldehyde at 4°C. Serial coronal brain sections absence of the interfering masking effects of light. (50 mm) through the SCN were cut from each brain on a vibratome, and In the present study, we investigated the involvement of the alternate sections were processed for either NPY or Fos immunohisto- IGL in entrainment of circadian rhythms by assessing the effects chemistry. The caudal portions of brains of IGL-lesioned and sham- of IGL lesions on body temperature rhythms of animals housed operated animals were cryoprotected in 30% sucrose formalin solution, under an SPP consisting of two 1 hr light pulses at times corre- and frozen coronal sections (30 mm) through the lateral geniculate nucleus were sliced on a cryostat and stained with thionin. sponding to dusk and dawn. The effect of IGL lesions on the NPY immunohistochemistry. Tissue sections were washed in cold 50 mM response of the SCN to the entraining light pulses was assessed Tris-buffered saline (TBS), pH 7.6 (Sigma, St. Louis, MO), and incu- using expression of the transcription factor Fos as a marker. The bated in a solution of 30% H2O2 (Sigma) in TBS for 30 min at room integrity of the GHT after IGL lesions was evaluated using temperature. These sections were then incubated in a solution of 0.3% immunohistochemical staining of NPY in the SCN. Triton X-100 (Sigma) in TBS (0.3% TTBS) with 4% normal goat serum Preliminary results have been published previously in abstract (NGS) (Vector, Burlingame, CA) on an orbital shaker for 1 hr at room temperature. Tissue sections were then incubated for 48 hr at 4°C with a form (Edelstein and Amir, 1997). rabbit polyclonal anti-NPY antibody (lot 960108-2; Peninsula, Belmont, MATERIALS AND METHODS CA). The antibody was diluted 1:5000 with a solution of 0.3% TTBS with 2% NGS. After incubation in the primary antibody, sections were rinsed Animals. Male Wistar rats (Charles River Canada, St. Constant, Quebec) in cold TBS and incubated for 1 hr at 4°C with a biotinylated anti-rabbit were used in all experiments. They were housed under 12 hr light/dark IgG made in goat (Vector), diluted 1:66 with 0.3% TTBS with 2% NGS. cycle (LD12:12) with free access to food and water for at least 2 weeks After incubation with secondary antibody, sections were rinsed in cold before surgery. TBS and incubated for 2 hr at 4°C with an avidin–biotin–peroxidase Surgery. Rats (275–300 gm) were anesthetized with sodium pentobar- complex (Vectastain Standard Elite ABC Kit, Vector). After incubation bital (65 mg/kg, i.p.) and implanted intraperitoneally with precalibrated telemetry transmitters (Mini Mitter Co., Sunriver, OR). Atropine sulfate with the ABC reagents, sections were rinsed with cold TBS, rinsed again (0.06 mg/0.1 ml, s.c.) was given 20 min before anesthesia. Bilateral with cold 50 mM Tris buffer, pH 7.6, and again for 10 min with 0.05% electrolytic lesions, aimed at the IGL, were made by passing 2 mA 3,39-diaminobenzidine (DAB) (Sigma) in 50 mM Tris-HCl. Sections were current for 15 sec through stainless steel electrodes, insulated except for then incubated on an orbital shaker for 10 min in DAB/Tris-HCl with the tip (Grass LM4 lesion maker). Electrode placements were at three 0.01% H2O2 and 8% NiCl2 (Sigma). After this final incubation, sections rostrocaudal positions on each side of the midline: 4.0, 4.7, and 5.4 mm were rinsed with cold TBS, wet-mounted onto gel-coated slides, dehy- posterior to bregma, 3.8 mm lateral to the midsagittal sinus, and 4.7 mm drated through a series of alcohols, soaked in xylene, and coverslipped ventral to dura.
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