Circadian rhythmicity restored by neural transplant. Immunocytochemical characterization of the graft and its integration with the host brain

Lehman, MN; Silver, Rae; Gladstone, W; Kahn, RM; Gibson, M.E.; Bittman, EL

doi:10.1523/jneurosci.07-06-01626.1987

Cited by 512 publications

(304 citation statements)

References 38 publications

(41 reference statements)

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“…Compelling evidence for a diffusible output signal derives from neural tissue transplantations in which the SCN from a fetal donor is implanted into the third ventricle of an adult, SCN-lesioned host. As mentioned previously, these grafts restore activity-related behaviors such as locomotor, drinking, and gnawing rhythms (Lehman et al, 1987;Ralph et al, 1990;Silver et al, 1990). That a diffusible signal is sufficient to restore locomotor rhythmicity in SCN-lesioned hosts was demonstrated by encapsulating donor SCN tissue in a membrane that prevented neural outgrowth while allowing the diffusion of signals between graft and host (Silver et al, 1996).…”

Section: Circadian Output and Orchestration Of Endocrine Function Difmentioning

confidence: 80%

“…The initial conclusion that the SCN serves as a brain master clock has been confirmed in the subsequent 30 years by converging lines of research involving in vivo, ex vivo, and in vitro studies carried out in many different laboratories. For example, transplants of donor SCN tissue into the brains of arrhythmic, SCN-lesioned hosts restore circadian rhythmicity in behavior (Lehman et al, 1987;Ralph et al, 1990). Importantly, rhythms are restored with the period of the donor SCN, indicating that the transplanted tissue does not act by restoring host brain function but that the "clock" is contained in the transplanted tissue.…”

Section: Identification Of a Brain "Clock": From Tissue To Genementioning

confidence: 99%

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The regulation of neuroendocrine function: Timing is everything

Kriegsfeld

Silver

2006

Hormones and Behavior

131

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Hormone secretion is highly organized temporally, achieving optimal biological functioning and health. The master clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus coordinates the timing of circadian rhythms, including daily control of hormone secretion. In the brain, the SCN drives hormone secretion. In some instances, SCN neurons make direct synaptic connections with neurosecretory neurons. In other instances, SCN signals set the phase of "clock genes" that regulate circadian function at the cellular level within neurosecretory cells. The protein products of these clock genes can also exert direct transcriptional control over neuroendocrine releasing factors. Clock genes and proteins are also expressed in peripheral endocrine organs providing additional modes of temporal control. Finally, the SCN signals endocrine glands via the autonomic nervous system, allowing for rapid regulation via multisynaptic pathways. Thus, the circadian system achieves temporal regulation of endocrine function by a combination of genetic, cellular, and neural regulatory mechanisms to ensure that each response occurs in its correct temporal niche. The availability of tools to assess the phase of molecular/cellular clocks and of powerful tract tracing methods to assess connections between "clock cells" and their targets provides an opportunity to examine circadian-controlled aspects of neurosecretion, in the search for general principles by which the endocrine system is organized. KeywordsCircadian; Diurnal; Endocrinel; Neurosecretion; Clock genes; Suprachiasmatic Circadian aspects of reproductionThe importance of circadian (about a day) timing in hormone production/secretion has been known since the 1950s when Everett and Sawyer determined that a stimulatory signal occurring during a narrow temporal window on the afternoon of proestrus is necessary for induction of ovulation later that night (Everett and Sawyer, 1950). Such close temporal organization is important for successful reproduction, as numerous hormone-dependent behavioral and physiological processes must be coordinated. If optimal temporal relationships are disrupted, pronounced deficits in fertility can result. For example, ovulation, behavioral estrus, fertilization, and pregnancy maintenance require a specific

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Section: Circadian Output and Orchestration Of Endocrine Function Difmentioning

confidence: 80%

Section: Identification Of a Brain "Clock": From Tissue To Genementioning

confidence: 99%

The regulation of neuroendocrine function: Timing is everything

Kriegsfeld

Silver

2006

Hormones and Behavior

131

View full text Add to dashboard Cite

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“…Neural transplantation has been a valuable approach to explore the potential for functional restoration after brain injury and damage (4,11) as well as to understand the normal functional organization of brain systems that mediate behavior and physiology (16). An example of the latter is in the field of circadian rhythms research, where transplantation has been used to investigate the signals and pathways by which the circadian clock communicates with the rest of the brain.…”

Section: Introductionmentioning

confidence: 99%

“…The endogenous biological clock that controls mammalian circadian rhythms is located in the suprachiasmatic nuclei of the anterior hypothalamus and regulates a wide variety of circadian rhythms in behavior, autonomic function, and neuroendocrine physiology (27). Fetal grafts of the SCN restore robust behavioral rhythms to SCN-lesioned rats and hamsters (9,12,16), and cross-genotype grafting between clock mutant and wild-type animals has shown that restored rhythms are due to the presence of the donor pacemaker (21) The precise mechanisms by which SCN grafts restore function are still under investigation, but there is evidence for both neural efferents (18) and diffusible factors (24) as mediators of circadian clock function. In order to assess graft outgrowth and map the pattern of host innervation, markers must be used to identify the grafted tissue and its efferents.…”

Section: Introductionmentioning

confidence: 99%

“…In order to assess graft outgrowth and map the pattern of host innervation, markers must be used to identify the grafted tissue and its efferents. For SCN graft studies, delineation of the graft and its borders is most often accomplished by the use of gross morphological features and specific neurochemical markers that characterize the SCN (1,14,16). Limitations to these techniques include the fact that graft and host tissue often appear to merge, that neurochemical markers are only expressed in a subpopulation of SCN cells and fibers, and that these markers are found in the host brain as well as the graft making it difficult to unambiguously identify their origin.…”

Section: Introductionmentioning

confidence: 99%

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Biotinylated Dextran Amine as a Marker for Fetal Hypothalamic Homografts and Their Efferents

Nelms

LeSauter

Silver

et al. 2002

Experimental Neurology

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We have explored the use of biotinylated dextran amine (BDA) as a marker for labeling fetal brain grafts and their connections with the host. As a model system we used transplantation of the hamster suprachiasmatic nucleus, the site of an endogenous biological clock governing circadian rhythms. Similar transplants into arrhythmic hosts have been shown to restore behavioral function with a period specific to the donor. For locomotor rhythms, efferent connections are not necessary. For other responses, including endocrine rhythms, efferent connections may be necessary. In order to visualize homografts and their efferents, injections of BDA, an anterograde tracer, were made into the anterior hypothalamic (AH) region containing the SCN or into the dorsal cortex (CTX) of fetal hamster brains. The fetal AH or CTX was microdissected out and stereotaxically implanted into the third ventricle of intact, adult hamsters. After 2, 4, 8, or 12 weeks, hosts were sacrificed and their brains were processed for detection of BDA by either histochemistry or immunofluorescence. BDA intensely labeled graft neurons, their dendrites, and axons with minimal or no spread to the adjacent host brain. Labeled graft axons could be followed for long distances (>1 mm) into the host brain and graft-derived varicosities formed close contacts with host neurons. BDA-labeled graft neurons, located at the perimeter of the graft, also extended dendrite-like processes into the host parenchyma. We conclude that BDA is a useful marker for fetal homografts and their efferents for survival times of less than 2 months.

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Organization of neural inputs to the suprachiasmatic nucleus in the rat

1997

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The circadian timing of the suprachiasmatic nucleus (SCN) is modulated by its neural inputs. In the present study, we examine the organization of the neural inputs to the rat SCN using both retrograde and anterograde tracing methods. After Fluoro-Gold injections into the SCN, retrogradely labeled neurons are present in a number of brain areas, including the infralimbic cortex, the lateral septum, the medial preoptic area, the subfornical organ, the paraventricular thalamus, the subparaventricular zone, the ventromedial hypothalamic nucleus, the posterior hypothalamic area, the intergeniculate leaflet, the olivary pretectal nucleus, the ventral subiculum, and the median raphe nuclei. In the anterograde tracing experiments, we observe three patterns of afferent termination within the SCN that correspond to the photic/raphe, limbic/hypothalamic, and thalamic inputs. The median raphe projection to the SCN terminates densely within the ventral subdivision and sparsely within the dorsal subdivision. Similarly, areas that receive photic input, such as the retina, the intergeniculate leaflet, and the pretectal area, densely innervate the ventral SCN but provide only minor innervation of the dorsal SCN. A complementary pattern of axonal labeling, with labeled fibers concentrated in the dorsal SCN, is observed after anterograde tracer injections into the hypothalamus and into limbic areas, such as the ventral subiculum and infralimbic cortex. A third, less common pattern of labeling, exemplified by the paraventricular thalamic afferents, consists of diffuse axonal labeling throughout the SCN. Our results show that the SCN afferent connections are topographically organized. These hodological differences may reflect a functional heterogeneity within the SCN.

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Circadian rhythmicity restored by neural transplant. Immunocytochemical characterization of the graft and its integration with the host brain

Cited by 512 publications

References 38 publications

The regulation of neuroendocrine function: Timing is everything

The regulation of neuroendocrine function: Timing is everything

Biotinylated Dextran Amine as a Marker for Fetal Hypothalamic Homografts and Their Efferents

Organization of neural inputs to the suprachiasmatic nucleus in the rat

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