Neuronal gene expression in the waking state: A role for the locus coeruleus

Science

Volumn 274, Issue 5290, 1996, Pages 1211-1215

  Cirelli, Chiara ^a   Pompeiano, Maria ^a   Tononi, Giulio ^a  

^a NEUROSCIENCES INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLIC AMP RESPONSIVE ELEMENT BINDING PROTEIN; NERVE GROWTH FACTOR; PROTEIN C FOS; TRANSCRIPTION FACTOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; GENE EXPRESSION REGULATION; LEARNING; LOCUS CERULEUS; NERVE CELL PLASTICITY; NERVE PROJECTION; NONHUMAN; NORADRENERGIC NERVE; ONCOGENE C FOS; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; RAT; REM SLEEP; WAKEFULNESS;

ADRENERGIC FIBERS; ANIMALS; BENZYLAMINES; BRAIN; CEREBRAL CORTEX; CYCLIC AMP RESPONSE ELEMENT-BINDING PROTEIN; DNA-BINDING PROTEINS; EARLY GROWTH RESPONSE PROTEIN 1; ELECTROENCEPHALOGRAPHY; GENE EXPRESSION REGULATION; GENES, FOS; GENES, IMMEDIATE-EARLY; HIPPOCAMPUS; IMMEDIATE-EARLY PROTEINS; LOCUS COERULEUS; NEURONS; NOREPINEPHRINE; OXIDOPAMINE; PHOSPHORYLATION; RATS; SLEEP; SLEEP DEPRIVATION; SYMPATHECTOMY, CHEMICAL; TRANSCRIPTION FACTORS; WAKEFULNESS;

ANIMALIA;

EID: 0029910282     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.274.5290.1211     Document Type: Article

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31. R. M. Gubits, T. M. Smith, J. L. Fairhurst, H. Yu. Mol. Brain Res. 6, 39 (1989); R. V. Bhat and J. M. Baraban, Eur. J. Pharmacol. 227, 447 (1992); S. L. Jones. J. Comp. Neurol. 325, 435 (1992); A. Carter, Eur. J. Pharmacol 244, 285 (1993); A. Pertovaara, R. Bravo, T. Herdegen, Neuroscience 54, 117 (1993); P.-J. Shen, T. C. D. Burazin, A. L. Gundlach, Mol. Brain Res. 28, 222 (1995). Note that many LC neurons also contain galanin and neuropeptide Y [reviewed by P. V. Holmes and J. N. Crawley, in Psychopharmacology. The Fourth Generation of Progress, F. E. Bloom and D. J. Kupfer, Eds. (Raven. New York, 1995). p. 2002], but it is not known whether these neuropeptides have any effect on IEG expression.
32. R. M. Gubits, T. M. Smith, J. L. Fairhurst, H. Yu. Mol. Brain Res. 6, 39 (1989); R. V. Bhat and J. M. Baraban, Eur. J. Pharmacol. 227, 447 (1992); S. L. Jones. J. Comp. Neurol. 325, 435 (1992); A. Carter, Eur. J. Pharmacol 244, 285 (1993); A. Pertovaara, R. Bravo, T. Herdegen, Neuroscience 54, 117 (1993); P.-J. Shen, T. C. D. Burazin, A. L. Gundlach, Mol. Brain Res. 28, 222 (1995). Note that many LC neurons also contain galanin and neuropeptide Y [reviewed by P. V. Holmes and J. N. Crawley, in Psychopharmacology. The Fourth Generation of Progress, F. E. Bloom and D. J. Kupfer, Eds. (Raven. New York, 1995). p. 2002], but it is not known whether these neuropeptides have any effect on IEG expression.
33. R. M. Gubits, T. M. Smith, J. L. Fairhurst, H. Yu. Mol. Brain Res. 6, 39 (1989); R. V. Bhat and J. M. Baraban, Eur. J. Pharmacol. 227, 447 (1992); S. L. Jones. J. Comp. Neurol. 325, 435 (1992); A. Carter, Eur. J. Pharmacol 244, 285 (1993); A. Pertovaara, R. Bravo, T. Herdegen, Neuroscience 54, 117 (1993); P.-J. Shen, T. C. D. Burazin, A. L. Gundlach, Mol. Brain Res. 28, 222 (1995). Note that many LC neurons also contain galanin and neuropeptide Y [reviewed by P. V. Holmes and J. N. Crawley, in Psychopharmacology. The Fourth Generation of Progress, F. E. Bloom and D. J. Kupfer, Eds. (Raven. New York, 1995). p. 2002], but it is not known whether these neuropeptides have any effect on IEG expression.
34. R. M. Gubits, T. M. Smith, J. L. Fairhurst, H. Yu. Mol. Brain Res. 6, 39 (1989); R. V. Bhat and J. M. Baraban, Eur. J. Pharmacol. 227, 447 (1992); S. L. Jones. J. Comp. Neurol. 325, 435 (1992); A. Carter, Eur. J. Pharmacol 244, 285 (1993); A. Pertovaara, R. Bravo, T. Herdegen, Neuroscience 54, 117 (1993); P.-J. Shen, T. C. D. Burazin, A. L. Gundlach, Mol. Brain Res. 28, 222 (1995). Note that many LC neurons also contain galanin and neuropeptide Y [reviewed by P. V. Holmes and J. N. Crawley, in Psychopharmacology. The Fourth Generation of Progress, F. E. Bloom and D. J. Kupfer, Eds. (Raven. New York, 1995). p. 2002], but it is not known whether these neuropeptides have any effect on IEG expression.
35. R. M. Gubits, T. M. Smith, J. L. Fairhurst, H. Yu. Mol. Brain Res. 6, 39 (1989); R. V. Bhat and J. M. Baraban, Eur. J. Pharmacol. 227, 447 (1992); S. L. Jones. J. Comp. Neurol. 325, 435 (1992); A. Carter, Eur. J. Pharmacol 244, 285 (1993); A. Pertovaara, R. Bravo, T. Herdegen, Neuroscience 54, 117 (1993); P.-J. Shen, T. C. D. Burazin, A. L. Gundlach, Mol. Brain Res. 28, 222 (1995). Note that many LC neurons also contain galanin and neuropeptide Y [reviewed by P. V. Holmes and J. N. Crawley, in Psychopharmacology. The Fourth Generation of Progress, F. E. Bloom and D. J. Kupfer, Eds. (Raven. New York, 1995). p. 2002], but it is not known whether these neuropeptides have any effect on IEG expression.
36. R. M. Gubits, T. M. Smith, J. L. Fairhurst, H. Yu. Mol. Brain Res. 6, 39 (1989); R. V. Bhat and J. M. Baraban, Eur. J. Pharmacol. 227, 447 (1992); S. L. Jones. J. Comp. Neurol. 325, 435 (1992); A. Carter, Eur. J. Pharmacol 244, 285 (1993); A. Pertovaara, R. Bravo, T. Herdegen, Neuroscience 54, 117 (1993); P.-J. Shen, T. C. D. Burazin, A. L. Gundlach, Mol. Brain Res. 28, 222 (1995). Note that many LC neurons also contain galanin and neuropeptide Y [reviewed by P. V. Holmes and J. N. Crawley, in Psychopharmacology. The Fourth Generation of Progress, F. E. Bloom and D. J. Kupfer, Eds. (Raven. New York, 1995). p. 2002], but it is not known whether these neuropeptides have any effect on IEG expression.
37. R. M. Gubits, T. M. Smith, J. L. Fairhurst, H. Yu. Mol. Brain Res. 6, 39 (1989); R. V. Bhat and J. M. Baraban, Eur. J. Pharmacol. 227, 447 (1992); S. L. Jones. J. Comp. Neurol. 325, 435 (1992); A. Carter, Eur. J. Pharmacol 244, 285 (1993); A. Pertovaara, R. Bravo, T. Herdegen, Neuroscience 54, 117 (1993); P.-J. Shen, T. C. D. Burazin, A. L. Gundlach, Mol. Brain Res. 28, 222 (1995). Note that many LC neurons also contain galanin and neuropeptide Y [reviewed by P. V. Holmes and J. N. Crawley, in Psychopharmacology. The Fourth Generation of Progress, F. E. Bloom and D. J. Kupfer, Eds. (Raven. New York, 1995). p. 2002], but it is not known whether these neuropeptides have any effect on IEG expression.
38. F. E. Bloom, S. Algeri, A. Groppetti, A. Revuelta, E. Costa, Science 166, 1284 (1969); N. J. Uretsky and L. L. Iversen, Nature 221, 557 (1969); R. M. Kostrzewa and D. M. Jacobowitz, Pharmacol. Rev. 26, 199 (1984). Male WKY rats under pentobarbital anesthesia [60 to 75 mg per kilogram of body weight, intraperitoneally (ip)] were implanted with screw electrodes in the skull to record the EEG and with silver electrodes in the neck muscles on both sides to record the electromyogram. During the same surgical session, rats were infused with 6-OHDA [Research Biochemicals International (RBI)] unilaterally into the left or right LC (N = 29) by way of a 24-g stainless steel needle connected to a 5-μl Hamilton syringe. The stereotaxic coordinates according to the atlas of Paxinos and Watson were 0.74 mm posterior to the interaural line, 7.5 mm below the dura, and 1.2 mm lateral to the midline. Rats were pretreated with the selective serotonin uptake inhibitor fluoxetine (10 mg/kg, ip) to prevent possible effects of 6-OHDA on serotoninergic terminals. The volume of 6-OHDA injected was 0.5 (N = 5). 1 (N = 6), 2 (N = 11), or 4 (N = 7) μl of a solution of 6-OHDA (2.5 μg/μl) in saline containing ascorbic acid (1 mg/ml). delivered over 5 min. The needle was inserted and removed in 5 min and left in place for an additional 5 min before and after the injection to avoid backdiffusion. After surgery, rats were housed individually in soundproof recording cages, where lighting and temperature were kept constant (hours of light and darkness, 12:12; light on at 10:00;24° ± 1°C; food and drink ad libitum). Immediately after recovery from anesthesia, rats were connected by means of a flexible cable and a commutator (Airflyte) to a Grass electroencephalograph (model 78), and recordings were made continuously for 2 to 3 weeks. Both right and left hemisphere EEGs were recorded. Each day from 09:30 to 10:00, rats were gently prodded with a small paintbrush to become familiar with the sleep deprivation procedure. Sleep deprivation was achieved by eliciting an orienting reaction whenever a slowing of the EEG was noted. Animal care was in accordance with institutional guidelines.
39. F. E. Bloom, S. Algeri, A. Groppetti, A. Revuelta, E. Costa, Science 166, 1284 (1969); N. J. Uretsky and L. L. Iversen, Nature 221, 557 (1969); R. M. Kostrzewa and D. M. Jacobowitz, Pharmacol. Rev. 26, 199 (1984). Male WKY rats under pentobarbital anesthesia [60 to 75 mg per kilogram of body weight, intraperitoneally (ip)] were implanted with screw electrodes in the skull to record the EEG and with silver electrodes in the neck muscles on both sides to record the electromyogram. During the same surgical session, rats were infused with 6-OHDA [Research Biochemicals International (RBI)] unilaterally into the left or right LC (N = 29) by way of a 24-g stainless steel needle connected to a 5-μl Hamilton syringe. The stereotaxic coordinates according to the atlas of Paxinos and Watson were 0.74 mm posterior to the interaural line, 7.5 mm below the dura, and 1.2 mm lateral to the midline. Rats were pretreated with the selective serotonin uptake inhibitor fluoxetine (10 mg/kg, ip) to prevent possible effects of 6-OHDA on serotoninergic terminals. The volume of 6-OHDA injected was 0.5 (N = 5). 1 (N = 6), 2 (N = 11), or 4 (N = 7) μl of a solution of 6-OHDA (2.5 μg/μl) in saline containing ascorbic acid (1 mg/ml). delivered over 5 min. The needle was inserted and removed in 5 min and left in place for an additional 5 min before and after the injection to avoid backdiffusion. After surgery, rats were housed individually in soundproof recording cages, where lighting and temperature were kept constant (hours of light and darkness, 12:12; light on at 10:00;24° ± 1°C; food and drink ad libitum). Immediately after recovery from anesthesia, rats were connected by means of a flexible cable and a commutator (Airflyte) to a Grass electroencephalograph (model 78), and recordings were made continuously for 2 to 3 weeks. Both right and left hemisphere EEGs were recorded. Each day from 09:30 to 10:00, rats were gently prodded with a small paintbrush to become familiar with the sleep deprivation procedure. Sleep deprivation was achieved by eliciting an orienting reaction whenever a slowing of the EEG was noted. Animal care was in accordance with institutional guidelines.
40. F. E. Bloom, S. Algeri, A. Groppetti, A. Revuelta, E. Costa, Science 166, 1284 (1969); N. J. Uretsky and L. L. Iversen, Nature 221, 557 (1969); R. M. Kostrzewa and D. M. Jacobowitz, Pharmacol. Rev. 26, 199 (1984). Male WKY rats under pentobarbital anesthesia [60 to 75 mg per kilogram of body weight, intraperitoneally (ip)] were implanted with screw electrodes in the skull to record the EEG and with silver electrodes in the neck muscles on both sides to record the electromyogram. During the same surgical session, rats were infused with 6-OHDA [Research Biochemicals International (RBI)] unilaterally into the left or right LC (N = 29) by way of a 24-g stainless steel needle connected to a 5-μl Hamilton syringe. The stereotaxic coordinates according to the atlas of Paxinos and Watson were 0.74 mm posterior to the interaural line, 7.5 mm below the dura, and 1.2 mm lateral to the midline. Rats were pretreated with the selective serotonin uptake inhibitor fluoxetine (10 mg/kg, ip) to prevent possible effects of 6-OHDA on serotoninergic terminals. The volume of 6-OHDA injected was 0.5 (N = 5). 1 (N = 6), 2 (N = 11), or 4 (N = 7) μl of a solution of 6-OHDA (2.5 μg/μl) in saline containing ascorbic acid (1 mg/ml). delivered over 5 min. The needle was inserted and removed in 5 min and left in place for an additional 5 min before and after the injection to avoid backdiffusion. After surgery, rats were housed individually in soundproof recording cages, where lighting and temperature were kept constant (hours of light and darkness, 12:12; light on at 10:00;24° ± 1°C; food and drink ad libitum). Immediately after recovery from anesthesia, rats were connected by means of a flexible cable and a commutator (Airflyte) to a Grass electroencephalograph (model 78), and recordings were made continuously for 2 to 3 weeks. Both right and left hemisphere EEGs were recorded. Each day from 09:30 to 10:00, rats were gently prodded with a small paintbrush to become familiar with the sleep deprivation procedure. Sleep deprivation was achieved by eliciting an orienting reaction whenever a slowing of the EEG was noted. Animal care was in accordance with institutional guidelines.
41. 2-terminal region of Fos proton and gave similar results [G. E. Hoffman, M. S. Smith, M. D. Fitzsimmons, Neuroprotocols 1, 52 (1992)]. Double-labeling experiments with antibodies against Fos (CRB, 1:1000) and glial fibrillary acidic protein [GFAP (Sigma), 1:400] or microtubule-associated protein 2 [MAP-2 (Sigma), 1:250] performed on a subset of sections showed that Fos-positive cells were neurons because they stained for MAP-2 but not for GFAP.
42. These animals showed no obvious behavioral alteration or changes in the sleep-waking cycle. Two weeks or more after surgery, percentages of recording time spent in different behavioral states [light hours: waking, 32 ± 2%; non-REM (NREM) sleep, 52 ± 2%; REM sleep, 16 ± 1 %; dark hours: waking, 67 ± 3%; NREM sleep, 28 ± 2%; REM sleep, 5 ± 1 %] were not significantly different from those of age-matched controls. Details of polysomnographic recordings and analysis are given in (3). In rats, intracerebroventricular injections of 6-OHDA associated with an almost complete bilateral decrease of cortical NE content caused only a transient decrease in waking [E. Hartmann and R. Chung, Nature 233, 425 (1971); P. Lidbrink, Brain Res. 74, 19 (1974)]. Bilateral LC lesions with 6-OHDA had no effects on the sleep-waking cycle [B. Roussel, J. F. Pujol, M, Jouvet, Arch. Ital. Biol. 114, 188 (1976)].
43. These animals showed no obvious behavioral alteration or changes in the sleep-waking cycle. Two weeks or more after surgery, percentages of recording time spent in different behavioral states [light hours: waking, 32 ± 2%; non-REM (NREM) sleep, 52 ± 2%; REM sleep, 16 ± 1 %; dark hours: waking, 67 ± 3%; NREM sleep, 28 ± 2%; REM sleep, 5 ± 1 %] were not significantly different from those of age-matched controls. Details of polysomnographic recordings and analysis are given in (3). In rats, intracerebroventricular injections of 6-OHDA associated with an almost complete bilateral decrease of cortical NE content caused only a transient decrease in waking [E. Hartmann and R. Chung, Nature 233, 425 (1971); P. Lidbrink, Brain Res. 74, 19 (1974)]. Bilateral LC lesions with 6-OHDA had no effects on the sleep-waking cycle [B. Roussel, J. F. Pujol, M, Jouvet, Arch. Ital. Biol. 114, 188 (1976)].
44. These animals showed no obvious behavioral alteration or changes in the sleep-waking cycle. Two weeks or more after surgery, percentages of recording time spent in different behavioral states [light hours: waking, 32 ± 2%; non-REM (NREM) sleep, 52 ± 2%; REM sleep, 16 ± 1 %; dark hours: waking, 67 ± 3%; NREM sleep, 28 ± 2%; REM sleep, 5 ± 1 %] were not significantly different from those of age-matched controls. Details of polysomnographic recordings and analysis are given in (3). In rats, intracerebroventricular injections of 6-OHDA associated with an almost complete bilateral decrease of cortical NE content caused only a transient decrease in waking [E. Hartmann and R. Chung, Nature 233, 425 (1971); P. Lidbrink, Brain Res. 74, 19 (1974)]. Bilateral LC lesions with 6-OHDA had no effects on the sleep-waking cycle [B. Roussel, J. F. Pujol, M, Jouvet, Arch. Ital. Biol. 114, 188 (1976)].
45. NE cell bodies and fibers were identified by incubating free-floating sections of the entire brain with a monoclonal antibody to tyrosine hydroxylase [TH (Boehringer), 1:1000 dilution] or, to ensure specificity, with a polyclonal antibody to dopamine-β-hydroxylase (Eugene, 1:1000 dilution). Immunoreactivity was detected with the avidin-biotin immunoperoxidase system (Vector) and nickel-enhanced diaminobenzidine. An effective unilateral LC lesion was scored if there was an almost complete disappearance of TH immunoreactivity in at least one sector of the LC of the injected side for at least four consecutive sections, whereas the amount of TH immunoreactivity in the LC of the intact side was comparable to that of control animate. The critical variable in determining the effectiveness of the injection was its site rather than Its volume. It has been reported that 6-OHDA injected into the LC can affect other noradrenergic groups [A. H. Frigelbrecht et al., J. Neurosci. Methods, 52; 57 (1994)]. Although this risk was reduced by the long injection times used in this study, the number of TH-positive cells in A5 and A7 as well as in A1 and A2 was counted in all animals, and TH and dopamine-β-hydroxylase staining in the hypothalamus were quantified by densitometry with an Image-1/Metamorph imaging system (Universal Imaging): Except for one animal with a slight reduction in the number of IH-positive cell bodies in A7 on the side of the injection, these values did not differ from those of control animals. Lesions of the dopaminergic system were also ruled out because the number of TH-positive cells in mesencephalic groups A8 and A10 was not modified. Decreases in TH and dopamine-β-hydroxylase staining in the cerebral cortex were also quantified by densitometry. Regions showing the strongest decrease in TH and dopamine-β-hydroxylase staining differed slightly from animal to animal, depending on the exact location of the 6-OHDA legion within the LC. Decreases in TH and dopamine-β-hydroxylase staining were evident ipsilateraily to the LC lesion, consistent with the observation that only a small fraction of NE fibers arise from the contralateral LC [B. D. Waterhouse, C.-S. Lin, R. A. Burne, D. J. Woodward, J. Comp. Neurol. 217, 418 (1983)]. Previous studies have shown that, in brain regions depleted of NE innervation from the LC by neurotoxic lesions, NE quantities measured by high-performance liquid chromatography were correspondingly depleted [J.-M. Fritschy and R. Grzanna, Prog. Brain Res. 88, 257 (1991)]. After 6-OHDA injections, no evidence of neuronal degeneration was found in cortical regions with cresyl violet staining, in agreement with previous reports [(J. C. Hedreen and J. P. Chalmers, Brain Res. 47, 1 (1972)].
46. NE cell bodies and fibers were identified by incubating free-floating sections of the entire brain with a monoclonal antibody to tyrosine hydroxylase [TH (Boehringer), 1:1000 dilution] or, to ensure specificity, with a polyclonal antibody to dopamine-β-hydroxylase (Eugene, 1:1000 dilution). Immunoreactivity was detected with the avidin-biotin immunoperoxidase system (Vector) and nickel-enhanced diaminobenzidine. An effective unilateral LC lesion was scored if there was an almost complete disappearance of TH immunoreactivity in at least one sector of the LC of the injected side for at least four consecutive sections, whereas the amount of TH immunoreactivity in the LC of the intact side was comparable to that of control animate. The critical variable in determining the effectiveness of the injection was its site rather than Its volume. It has been reported that 6-OHDA injected into the LC can affect other noradrenergic groups [A. H. Frigelbrecht et al., J. Neurosci. Methods, 52; 57 (1994)]. Although this risk was reduced by the long injection times used in this study, the number of TH-positive cells in A5 and A7 as well as in A1 and A2 was counted in all animals, and TH and dopamine-β-hydroxylase staining in the hypothalamus were quantified by densitometry with an Image-1/Metamorph imaging system (Universal Imaging): Except for one animal with a slight reduction in the number of IH-positive cell bodies in A7 on the side of the injection, these values did not differ from those of control animals. Lesions of the dopaminergic system were also ruled out because the number of TH-positive cells in mesencephalic groups A8 and A10 was not modified. Decreases in TH and dopamine-β-hydroxylase staining in the cerebral cortex were also quantified by densitometry. Regions showing the strongest decrease in TH and dopamine-β-hydroxylase staining differed slightly from animal to animal, depending on the exact location of the 6-OHDA legion within the LC. Decreases in TH and dopamine-β-hydroxylase staining were evident ipsilateraily to the LC lesion, consistent with the observation that only a small fraction of NE fibers arise from the contralateral LC [B. D. Waterhouse, C.-S. Lin, R. A. Burne, D. J. Woodward, J. Comp. Neurol. 217, 418 (1983)]. Previous studies have shown that, in brain regions depleted of NE innervation from the LC by neurotoxic lesions, NE quantities measured by high-performance liquid chromatography were correspondingly depleted [J.-M. Fritschy and R. Grzanna, Prog. Brain Res. 88, 257 (1991)]. After 6-OHDA injections, no evidence of neuronal degeneration was found in cortical regions with cresyl violet staining, in agreement with previous reports [(J. C. Hedreen and J. P. Chalmers, Brain Res. 47, 1 (1972)].
47. NE cell bodies and fibers were identified by incubating free-floating sections of the entire brain with a monoclonal antibody to tyrosine hydroxylase [TH (Boehringer), 1:1000 dilution] or, to ensure specificity, with a polyclonal antibody to dopamine-β-hydroxylase (Eugene, 1:1000 dilution). Immunoreactivity was detected with the avidin-biotin immunoperoxidase system (Vector) and nickel-enhanced diaminobenzidine. An effective unilateral LC lesion was scored if there was an almost complete disappearance of TH immunoreactivity in at least one sector of the LC of the injected side for at least four consecutive sections, whereas the amount of TH immunoreactivity in the LC of the intact side was comparable to that of control animate. The critical variable in determining the effectiveness of the injection was its site rather than Its volume. It has been reported that 6-OHDA injected into the LC can affect other noradrenergic groups [A. H. Frigelbrecht et al., J. Neurosci. Methods, 52; 57 (1994)]. Although this risk was reduced by the long injection times used in this study, the number of TH-positive cells in A5 and A7 as well as in A1 and A2 was counted in all animals, and TH and dopamine-β-hydroxylase staining in the hypothalamus were quantified by densitometry with an Image-1/Metamorph imaging system (Universal Imaging): Except for one animal with a slight reduction in the number of IH-positive cell bodies in A7 on the side of the injection, these values did not differ from those of control animals. Lesions of the dopaminergic system were also ruled out because the number of TH-positive cells in mesencephalic groups A8 and A10 was not modified. Decreases in TH and dopamine-β-hydroxylase staining in the cerebral cortex were also quantified by densitometry. Regions showing the strongest decrease in TH and dopamine-β-hydroxylase staining differed slightly from animal to animal, depending on the exact location of the 6-OHDA legion within the LC. Decreases in TH and dopamine-β-hydroxylase staining were evident ipsilateraily to the LC lesion, consistent with the observation that only a small fraction of NE fibers arise from the contralateral LC [B. D. Waterhouse, C.-S. Lin, R. A. Burne, D. J. Woodward, J. Comp. Neurol. 217, 418 (1983)]. Previous studies have shown that, in brain regions depleted of NE innervation from the LC by neurotoxic lesions, NE quantities measured by high-performance liquid chromatography were correspondingly depleted [J.-M. Fritschy and R. Grzanna, Prog. Brain Res. 88, 257 (1991)]. After 6-OHDA injections, no evidence of neuronal degeneration was found in cortical regions with cresyl violet staining, in agreement with previous reports [(J. C. Hedreen and J. P. Chalmers, Brain Res. 47, 1 (1972)].
48. NE cell bodies and fibers were identified by incubating free-floating sections of the entire brain with a monoclonal antibody to tyrosine hydroxylase [TH (Boehringer), 1:1000 dilution] or, to ensure specificity, with a polyclonal antibody to dopamine-β-hydroxylase (Eugene, 1:1000 dilution). Immunoreactivity was detected with the avidin-biotin immunoperoxidase system (Vector) and nickel-enhanced diaminobenzidine. An effective unilateral LC lesion was scored if there was an almost complete disappearance of TH immunoreactivity in at least one sector of the LC of the injected side for at least four consecutive sections, whereas the amount of TH immunoreactivity in the LC of the intact side was comparable to that of control animate. The critical variable in determining the effectiveness of the injection was its site rather than Its volume. It has been reported that 6-OHDA injected into the LC can affect other noradrenergic groups [A. H. Frigelbrecht et al., J. Neurosci. Methods, 52; 57 (1994)]. Although this risk was reduced by the long injection times used in this study, the number of TH-positive cells in A5 and A7 as well as in A1 and A2 was counted in all animals, and TH and dopamine-β-hydroxylase staining in the hypothalamus were quantified by densitometry with an Image-1/Metamorph imaging system (Universal Imaging): Except for one animal with a slight reduction in the number of IH-positive cell bodies in A7 on the side of the injection, these values did not differ from those of control animals. Lesions of the dopaminergic system were also ruled out because the number of TH-positive cells in mesencephalic groups A8 and A10 was not modified. Decreases in TH and dopamine-β-hydroxylase staining in the cerebral cortex were also quantified by densitometry. Regions showing the strongest decrease in TH and dopamine-β-hydroxylase staining differed slightly from animal to animal, depending on the exact location of the 6-OHDA legion within the LC. Decreases in TH and dopamine-β-hydroxylase staining were evident ipsilateraily to the LC lesion, consistent with the observation that only a small fraction of NE fibers arise from the contralateral LC [B. D. Waterhouse, C.-S. Lin, R. A. Burne, D. J. Woodward, J. Comp. Neurol. 217, 418 (1983)]. Previous studies have shown that, in brain regions depleted of NE innervation from the LC by neurotoxic lesions, NE quantities measured by high-performance liquid chromatography were correspondingly depleted [J.-M. Fritschy and R. Grzanna, Prog. Brain Res. 88, 257 (1991)]. After 6-OHDA injections, no evidence of neuronal degeneration was found in cortical regions with cresyl violet staining, in agreement with previous reports [(J. C. Hedreen and J. P. Chalmers, Brain Res. 47, 1 (1972)].
49. Cell counting was performed with the Image-1/ Metamorph imaging system as described (3) by observers blind to the origin of the sections. In rats with unilateral lesions of the LC killed after 3 hours of sleep, the amounts of Fos staining were uniformly low and indistinguishable from those observed in sleeping controls. We did not observe differences between the effects of right and left LC lesions. In two animals, presumably because of a ventricular injection, as suggested by the position of the cannula track, NE cell bodies in the LC and NE fibers in the cortex were depleted bilaterally. In these animals, Fos staining after sleep deprivation was bilaterally low.
50. C. Cirelli, M. Pompeiano, G. Tononi, data not shown.
51. To detect c-Fos mRNA by nonradioactive in situ hybridization, we quickly removed brains and froze them without perfusion. Sections were mounted on slides, fixed, incubated with predigested Pronase, washed in phosphate-buffered saline, and then incubated overnight at 55°C with a c-Fos digoxigeninlabeled RNA probe (400 ng/ml). The probe was prepared by in vitro transcription of the c-Fos exon 4 mouse cDNA (bases 2437 to 2187) in pTRIPLE-scriptTM vector (Ambion) with T7 RNA polymerase (Promega). After hybridization, sections were rinsed and incubated with an antibody to digoxigenin tagged with alkaline phosphatase (Boehringer); a color reaction was developed by using nitroblue tetrazolium as substrate [for details see C. Cirelli, M. Pompeiano, P. Arrighi, G. Tononi, Arch. Ital. Biol. 133, 143 (1995)].
52. R. M. Gubits, T. M. Smith, J. L. Fairhurst, H. Yu, Mol. Brain Res. 6, 39 (1989); G. Bing, D. Filer, J. C. Miller, E. A. Stone, ibid. 11, 43 (1991); E. A. Stone, Y. Zhang, S. John, D. Filer, G. Bing, Brain Res. 603, 181 (1993). It should be noted, however, that sleep deprivation for 3 hours is not associated with signs of stress, especially in trained animals (see I. Tobler, R. Murison, R. Ursin, H. Ursin, A. A. Borbély, Neurosci. Lett. 35, 297 (1983)].
53. R. M. Gubits, T. M. Smith, J. L. Fairhurst, H. Yu, Mol. Brain Res. 6, 39 (1989); G. Bing, D. Filer, J. C. Miller, E. A. Stone, ibid. 11, 43 (1991); E. A. Stone, Y. Zhang, S. John, D. Filer, G. Bing, Brain Res. 603, 181 (1993). It should be noted, however, that sleep deprivation for 3 hours is not associated with signs of stress, especially in trained animals (see I. Tobler, R. Murison, R. Ursin, H. Ursin, A. A. Borbély, Neurosci. Lett. 35, 297 (1983)].
54. R. M. Gubits, T. M. Smith, J. L. Fairhurst, H. Yu, Mol. Brain Res. 6, 39 (1989); G. Bing, D. Filer, J. C. Miller, E. A. Stone, ibid. 11, 43 (1991); E. A. Stone, Y. Zhang, S. John, D. Filer, G. Bing, Brain Res. 603, 181 (1993). It should be noted, however, that sleep deprivation for 3 hours is not associated with signs of stress, especially in trained animals (see I. Tobler, R. Murison, R. Ursin, H. Ursin, A. A. Borbély, Neurosci. Lett. 35, 297 (1983)].
55. R. M. Gubits, T. M. Smith, J. L. Fairhurst, H. Yu, Mol. Brain Res. 6, 39 (1989); G. Bing, D. Filer, J. C. Miller, E. A. Stone, ibid. 11, 43 (1991); E. A. Stone, Y. Zhang, S. John, D. Filer, G. Bing, Brain Res. 603, 181 (1993). It should be noted, however, that sleep deprivation for 3 hours is not associated with signs of stress, especially in trained animals (see I. Tobler, R. Murison, R. Ursin, H. Ursin, A. A. Borbély, Neurosci. Lett. 35, 297 (1983)].
56. A systematic quantification of Fos and NGFI-A expression in the brain after waking induced by sleep deprivation during the light hours or after spontaneous waking during the dark hours is found in (4) and (3), respectively.
57. An increase in IEG expression after periods of sleep deprivation has been reported in B. F. O'Hara, K. A. Young, F. L. Watson, H. Craig Heller, T. S. Kilduff, Sleep 16, 1 (1993); M. Pompeiano, C. Cirelli, G. Tonini, Soc. Neurosci. Abstr. 19, 572 (1993).
58. An increase in IEG expression after periods of sleep deprivation has been reported in B. F. O'Hara, K. A. Young, F. L. Watson, H. Craig Heller, T. S. Kilduff, Sleep 16, 1 (1993); M. Pompeiano, C. Cirelli, G. Tonini, Soc. Neurosci. Abstr. 19, 572 (1993).
59. J. Milbrandt, Science 238, 797 (1987); K.-H. Schlingensiepen, K. Lüno, W. Brysch, Neurosci. Lett. 122, 67 (1991). NGFI-A mRNA concentrations also respond to manipulations of the NE system [G. Bing, D. Filer, J. C. Miller, E. A. Stone, Mol. Brain Res. 11, 43 (1991); R. V. Bhat and J. M. Baraban, Eur. J. Pharmacol. 227, 447 (1992); P.-J. Shen, T. C. D. Burazin, A. L. Gundlach, Mol. Brain Res. 28, 222 (1995)].
60. J. Milbrandt, Science 238, 797 (1987); K.-H. Schlingensiepen, K. Lüno, W. Brysch, Neurosci. Lett. 122, 67 (1991). NGFI-A mRNA concentrations also respond to manipulations of the NE system [G. Bing, D. Filer, J. C. Miller, E. A. Stone, Mol. Brain Res. 11, 43 (1991); R. V. Bhat and J. M. Baraban, Eur. J. Pharmacol. 227, 447 (1992); P.-J. Shen, T. C. D. Burazin, A. L. Gundlach, Mol. Brain Res. 28, 222 (1995)].
61. J. Milbrandt, Science 238, 797 (1987); K.-H. Schlingensiepen, K. Lüno, W. Brysch, Neurosci. Lett. 122, 67 (1991). NGFI-A mRNA concentrations also respond to manipulations of the NE system [G. Bing, D. Filer, J. C. Miller, E. A. Stone, Mol. Brain Res. 11, 43 (1991); R. V. Bhat and J. M. Baraban, Eur. J. Pharmacol. 227, 447 (1992); P.-J. Shen, T. C. D. Burazin, A. L. Gundlach, Mol. Brain Res. 28, 222 (1995)].
62. J. Milbrandt, Science 238, 797 (1987); K.-H. Schlingensiepen, K. Lüno, W. Brysch, Neurosci. Lett. 122, 67 (1991). NGFI-A mRNA concentrations also respond to manipulations of the NE system [G. Bing, D. Filer, J. C. Miller, E. A. Stone, Mol. Brain Res. 11, 43 (1991); R. V. Bhat and J. M. Baraban, Eur. J. Pharmacol. 227, 447 (1992); P.-J. Shen, T. C. D. Burazin, A. L. Gundlach, Mol. Brain Res. 28, 222 (1995)].
63. J. Milbrandt, Science 238, 797 (1987); K.-H. Schlingensiepen, K. Lüno, W. Brysch, Neurosci. Lett. 122, 67 (1991). NGFI-A mRNA concentrations also respond to manipulations of the NE system [G. Bing, D. Filer, J. C. Miller, E. A. Stone, Mol. Brain Res. 11, 43 (1991); R. V. Bhat and J. M. Baraban, Eur. J. Pharmacol. 227, 447 (1992); P.-J. Shen, T. C. D. Burazin, A. L. Gundlach, Mol. Brain Res. 28, 222 (1995)].
64. P. F. Worley et al., Proc. Natl. Acad. Sci. U.S.A. 88, 5106(1991).
65. P. Sassone-Corsi, J. Visvader, L. Ferland, P. L Mellon, I. M. Verma, Genes Dev. 2, 1529 (1988); M. Sheng and M. E. Greenberg, Neuron 4, 477 (1990); K. M. Sakamoto et al., Oncogens 6, 867 (1991).
66. P. Sassone-Corsi, J. Visvader, L. Ferland, P. L Mellon, I. M. Verma, Genes Dev. 2, 1529 (1988); M. Sheng and M. E. Greenberg, Neuron 4, 477 (1990); K. M. Sakamoto et al., Oncogens 6, 867 (1991).
67. P. Sassone-Corsi, J. Visvader, L. Ferland, P. L Mellon, I. M. Verma, Genes Dev. 2, 1529 (1988); M. Sheng and M. E. Greenberg, Neuron 4, 477 (1990); K. M. Sakamoto et al., Oncogens 6, 867 (1991).
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69. Like β-adrenergic receptors, Fos-positive cells were most numerous in layers II, III, and Vl [compare with J. M. Palacios, W. S. Young III, M. J. Kuhar, Science 208, 1378 (1980); T. C. Rainbow. B. Parsons, B. B. Wolfe, Proc. Natl. Acad. Sci. U.S.A. 81, 1585 (1984); C. Aoki, T. H. Joh, V. M. Pickel, Brain Res. 437, 264 (1987)].
70. Like β-adrenergic receptors, Fos-positive cells were most numerous in layers II, III, and Vl [compare with J. M. Palacios, W. S. Young III, M. J. Kuhar, Science 208, 1378 (1980); T. C. Rainbow. B. Parsons, B. B. Wolfe, Proc. Natl. Acad. Sci. U.S.A. 81, 1585 (1984); C. Aoki, T. H. Joh, V. M. Pickel, Brain Res. 437, 264 (1987)].
71. R. S. Duman and E. J. Nestler, in Psychopharmacology: The Fourth Generation of Progress, F. E. Bloom and D. J. Kupfer, Eds. (Raven, New York, 1995), pp. 303-320.
72. K. M. Rosen, M. A. McCormack, L. Villa-Kornaroff, G. D. Mower, Proc. Natl. Acad. Sci. U.S.A. 89, 5437 (1992). Consistent with these results, in a rat in which the trigeminothalamic tract was accidentally lesioned, we observed a marked reduction of Fos, NGFI-A, and P-CREB staining localized to the contralateral somatosensory cortex in the presence of normal NE innervation (14).
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76. Rats implanted with electrodes for polysomnographic recordings were pretreated with fluoxetine [see (9)] and then injected ip with DSP-4 (RBI, 50mg/kg). Continuous recordings were made 4 to 6 days before and 8 to 10 days after the injection. An examination of sections stained for TH and dopamine-β-hydroxylase immunocytochemistry showed that nearly all NE terminals had disappeared in neocortex, hippocampal formation, olfactory bulbs, thalamus with the exception of the paraventricular nucleus, tectum, and cerebellum, whereas amygdala, septum, and hypothalamus were largely spared. Percentages of waking and sleep did not differ significantly before (light hours: waking, 36 ± 2%; NREM sleep, 49 ± 2%; REM sleep, 15 ± 1%; dark hours: waking, 68 ± 4%; NREM sleep, 28 ± 3%; REM sleep, 4 ± 1%) and 8 to 10 days after (light hours: waking, 34 ± 1%; NREM sleep, 52 ± 2%; REM sleep, 14 ± 1%; dark hours: waking, 58 ± 1%; NREM sleep, 35 ± 1%; REM sleep, 7 ± 1%) the injection [compare with J. M. Monti, L. D'Angelo, H. Jantos, L. Barbeito, V. Abó, Sleep 11, 370 (1988)].
77. Two gold-plated, round-tipped miniature screw electrodes implanted over the frontal cortex (2 mm anterior to the bregma and 2 mm lateral to the midline) and over the occipital cortex (4 mm posterior to the bregma and 3.8 mm lateral to the midline) were used to record the cortical EEG. EEG signals were low-pass filtered (-3 dB at 30 Hz. 24 dB per octave), analog-to-digital converted (sampling rate, 128 Hz), and subjected to spectral analysis. EEG power density values were computed for successive 4-s periods (24 hours of recording for each animal) in the frequency range from 0.25 to 25 Hz (collapsed into 0.5-Hz bins between 0.25 and 5 Hz and into 1-Hz bins between 5.25 and 25 Hz). Recording epochs showing EEG artifacts were not used for spectral analysis.
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80. Because the percentages of recording time spent in different behavioral states as well as overall EEG patterns of waking and sleep 8 to 10 days after lesioning of LC terminals were indistinguishable from those before the lesions, our results confirm that other reticular-activating systems in addition to the NE system are sufficient for maintaining long-term EEG activation [B. E. Jones, S. T. Harper, A. E. Halaris, Brain Res. 124, 473 (1977); T. E. Robinson, C. H. Vanderwolf, B. A. Pappas, ibid. 138, 75 (1977); P. Riekkinen Jr., M. Riekkinen, A. Valjakka, P. Riekkinen, J. Sirviö, ibid. 570, 293 (1992)]. Short-term changes in LC activity, however, have definite effects on the EEG. Acute bilateral, but not unilateral, inactivation of the LC is associated with slowing of the EEG [R. Cespuglio, M. E. Gomez, H. Faradji, M. Jouvet, Electroencephalogr. Clin. Neurophysiol. 54, 570 (1982); C. W. Berridge, M. E. Page, R. J. Valentino, S. L. Foote, Neuroscience 55, 381 (1993)], and neurochemical activation of the LC is followed by EEG activation [C. W. Berridge and S. L. Foote, J. Neurosci. 11, 3135 (1991)].
81. Because the percentages of recording time spent in different behavioral states as well as overall EEG patterns of waking and sleep 8 to 10 days after lesioning of LC terminals were indistinguishable from those before the lesions, our results confirm that other reticular-activating systems in addition to the NE system are sufficient for maintaining long-term EEG activation [B. E. Jones, S. T. Harper, A. E. Halaris, Brain Res. 124, 473 (1977); T. E. Robinson, C. H. Vanderwolf, B. A. Pappas, ibid. 138, 75 (1977); P. Riekkinen Jr., M. Riekkinen, A. Valjakka, P. Riekkinen, J. Sirviö, ibid. 570, 293 (1992)]. Short-term changes in LC activity, however, have definite effects on the EEG. Acute bilateral, but not unilateral, inactivation of the LC is associated with slowing of the EEG [R. Cespuglio, M. E. Gomez, H. Faradji, M. Jouvet, Electroencephalogr. Clin. Neurophysiol. 54, 570 (1982); C. W. Berridge, M. E. Page, R. J. Valentino, S. L. Foote, Neuroscience 55, 381 (1993)], and neurochemical activation of the LC is followed by EEG activation [C. W. Berridge and S. L. Foote, J. Neurosci. 11, 3135 (1991)].
82. Because the percentages of recording time spent in different behavioral states as well as overall EEG patterns of waking and sleep 8 to 10 days after lesioning of LC terminals were indistinguishable from those before the lesions, our results confirm that other reticular-activating systems in addition to the NE system are sufficient for maintaining long-term EEG activation [B. E. Jones, S. T. Harper, A. E. Halaris, Brain Res. 124, 473 (1977); T. E. Robinson, C. H. Vanderwolf, B. A. Pappas, ibid. 138, 75 (1977); P. Riekkinen Jr., M. Riekkinen, A. Valjakka, P. Riekkinen, J. Sirviö, ibid. 570, 293 (1992)]. Short-term changes in LC activity, however, have definite effects on the EEG. Acute bilateral, but not unilateral, inactivation of the LC is associated with slowing of the EEG [R. Cespuglio, M. E. Gomez, H. Faradji, M. Jouvet, Electroencephalogr. Clin. Neurophysiol. 54, 570 (1982); C. W. Berridge, M. E. Page, R. J. Valentino, S. L. Foote, Neuroscience 55, 381 (1993)], and neurochemical activation of the LC is followed by EEG activation [C. W. Berridge and S. L. Foote, J. Neurosci. 11, 3135 (1991)].
83. Because the percentages of recording time spent in different behavioral states as well as overall EEG patterns of waking and sleep 8 to 10 days after lesioning of LC terminals were indistinguishable from those before the lesions, our results confirm that other reticular-activating systems in addition to the NE system are sufficient for maintaining long-term EEG activation [B. E. Jones, S. T. Harper, A. E. Halaris, Brain Res. 124, 473 (1977); T. E. Robinson, C. H. Vanderwolf, B. A. Pappas, ibid. 138, 75 (1977); P. Riekkinen Jr., M. Riekkinen, A. Valjakka, P. Riekkinen, J. Sirviö, ibid. 570, 293 (1992)]. Short-term changes in LC activity, however, have definite effects on the EEG. Acute bilateral, but not unilateral, inactivation of the LC is associated with slowing of the EEG [R. Cespuglio, M. E. Gomez, H. Faradji, M. Jouvet, Electroencephalogr. Clin. Neurophysiol. 54, 570 (1982); C. W. Berridge, M. E. Page, R. J. Valentino, S. L. Foote, Neuroscience 55, 381 (1993)], and neurochemical activation of the LC is followed by EEG activation [C. W. Berridge and S. L. Foote, J. Neurosci. 11, 3135 (1991)].
84. Because the percentages of recording time spent in different behavioral states as well as overall EEG patterns of waking and sleep 8 to 10 days after lesioning of LC terminals were indistinguishable from those before the lesions, our results confirm that other reticular-activating systems in addition to the NE system are sufficient for maintaining long-term EEG activation [B. E. Jones, S. T. Harper, A. E. Halaris, Brain Res. 124, 473 (1977); T. E. Robinson, C. H. Vanderwolf, B. A. Pappas, ibid. 138, 75 (1977); P. Riekkinen Jr., M. Riekkinen, A. Valjakka, P. Riekkinen, J. Sirviö, ibid. 570, 293 (1992)]. Short-term changes in LC activity, however, have definite effects on the EEG. Acute bilateral, but not unilateral, inactivation of the LC is associated with slowing of the EEG [R. Cespuglio, M. E. Gomez, H. Faradji, M. Jouvet, Electroencephalogr. Clin. Neurophysiol. 54, 570 (1982); C. W. Berridge, M. E. Page, R. J. Valentino, S. L. Foote, Neuroscience 55, 381 (1993)], and neurochemical activation of the LC is followed by EEG activation [C. W. Berridge and S. L. Foote, J. Neurosci. 11, 3135 (1991)].
85. Because the percentages of recording time spent in different behavioral states as well as overall EEG patterns of waking and sleep 8 to 10 days after lesioning of LC terminals were indistinguishable from those before the lesions, our results confirm that other reticular-activating systems in addition to the NE system are sufficient for maintaining long-term EEG activation [B. E. Jones, S. T. Harper, A. E. Halaris, Brain Res. 124, 473 (1977); T. E. Robinson, C. H. Vanderwolf, B. A. Pappas, ibid. 138, 75 (1977); P. Riekkinen Jr., M. Riekkinen, A. Valjakka, P. Riekkinen, J. Sirviö, ibid. 570, 293 (1992)]. Short-term changes in LC activity, however, have definite effects on the EEG. Acute bilateral, but not unilateral, inactivation of the LC is associated with slowing of the EEG [R. Cespuglio, M. E. Gomez, H. Faradji, M. Jouvet, Electroencephalogr. Clin. Neurophysiol. 54, 570 (1982); C. W. Berridge, M. E. Page, R. J. Valentino, S. L. Foote, Neuroscience 55, 381 (1993)], and neurochemical activation of the LC is followed by EEG activation [C. W. Berridge and S. L. Foote, J. Neurosci. 11, 3135 (1991)].
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90. S. P. R. Rose, Trends Neurosci. 14, 390 (1991); P. A. Brennan, D. Hancock, E. B. Keverne, Neuroscience 49, 277 (1992); L. Kaczmarek, Behav. Neural Biol. 57, 263 (1992); W. C. Abraham et al., Neuroscience 56, 717 (1993); C. Heurteaux, C. Messier, C. Destrade, M. Lazdunski, Mol. Brain Res. 18, 17 (1993); B.-K. Kaang, E. R. Kandel, S. G. N. Grant, Neuron 10, 427 (1993); C. M. Alberini, M. Ghirardi, R. Metz, E. R. Kandel, Cell 76,1099 (1994); E. D. Jarvis, C. V. Mello, F. Nottebohm, Learning Memory 2, 62 (1995); Y. Watanabe et al., J. Neurosci. 16, 3827 (1996); for reviews, see A. J. Silva and P. K. Giese, Curr. Opin. Neurobiol. 4, 413 (1994); P. Hughes and M. Dragunow, Pharmacol. Rev. 47, 133 (1995); and J. C. P. Yin and T. Tully, Curr. Opin. Neurobiol. 6, 264 (1996).
91. S. P. R. Rose, Trends Neurosci. 14, 390 (1991); P. A. Brennan, D. Hancock, E. B. Keverne, Neuroscience 49, 277 (1992); L. Kaczmarek, Behav. Neural Biol. 57, 263 (1992); W. C. Abraham et al., Neuroscience 56, 717 (1993); C. Heurteaux, C. Messier, C. Destrade, M. Lazdunski, Mol. Brain Res. 18, 17 (1993); B.-K. Kaang, E. R. Kandel, S. G. N. Grant, Neuron 10, 427 (1993); C. M. Alberini, M. Ghirardi, R. Metz, E. R. Kandel, Cell 76,1099 (1994); E. D. Jarvis, C. V. Mello, F. Nottebohm, Learning Memory 2, 62 (1995); Y. Watanabe et al., J. Neurosci. 16, 3827 (1996); for reviews, see A. J. Silva and P. K. Giese, Curr. Opin. Neurobiol. 4, 413 (1994); P. Hughes and M. Dragunow, Pharmacol. Rev. 47, 133 (1995); and J. C. P. Yin and T. Tully, Curr. Opin. Neurobiol. 6, 264 (1996).
92. S. P. R. Rose, Trends Neurosci. 14, 390 (1991); P. A. Brennan, D. Hancock, E. B. Keverne, Neuroscience 49, 277 (1992); L. Kaczmarek, Behav. Neural Biol. 57, 263 (1992); W. C. Abraham et al., Neuroscience 56, 717 (1993); C. Heurteaux, C. Messier, C. Destrade, M. Lazdunski, Mol. Brain Res. 18, 17 (1993); B.-K. Kaang, E. R. Kandel, S. G. N. Grant, Neuron 10, 427 (1993); C. M. Alberini, M. Ghirardi, R. Metz, E. R. Kandel, Cell 76,1099 (1994); E. D. Jarvis, C. V. Mello, F. Nottebohm, Learning Memory 2, 62 (1995); Y. Watanabe et al., J. Neurosci. 16, 3827 (1996); for reviews, see A. J. Silva and P. K. Giese, Curr. Opin. Neurobiol. 4, 413 (1994); P. Hughes and M. Dragunow, Pharmacol. Rev. 47, 133 (1995); and J. C. P. Yin and T. Tully, Curr. Opin. Neurobiol. 6, 264 (1996).
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114. We thank G. A. Davis for his contribution to the surgical and histological part of this work. We also thank several Fellows of The Neurosciences Institute for useful comments. This work was carried out as part of the experimental neurobiology program at the Institute, which is supported by the Neurosciences Research Foundation. The Foundation receives major support for this program from Sandoz Pharmaceuticals.