Summary Currently available evidence strongly supports the position that the initiating event in Alzheimer's disease (AD) is related to abnormal processing of β-amyloid (Aβ) peptide, ultimately leading to formation of Aβ plaques in the brain. This process occurs while individuals are still cognitively normal. Biomarkers of brain β-amyloidosis are reductions in CSF Aβ 42 and increased amyloid PET tracer retention. After a lag period, which varies from patient to patient, neuronal dysfunction and neurodegeneration become the dominant pathological processes. Biomarkers of neuronal injury and neurodegeneration are increased CSF tau and structural MRI measures of cerebral atrophy. Neurodegeneration is accompanied by synaptic dysfunction, which is indicated by decreased fluorodeoxyglucose uptake on PET. We propose a model that relates disease stage to AD biomarkers in which Aβ biomarkers become abnormal first, before neurodegenerative biomarkers and cognitive symptoms, and neurodegenerative biomarkers become abnormal later, and correlate with clinical symptom severity.

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Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade

Functional brain imaging in humans has revealed task-specific increases in brain activity that are associated with various mental activities. In the same studies, mysterious, task-independent decreases have also frequently been encountered, especially when the tasks of interest have been compared with a passive state, such as simple fixation or eyes closed. These decreases have raised the possibility that there might be a baseline or resting state of brain function involving a specific set of mental operations. We explore this possibility, including the manner in which we might define a baseline and the implications of such a baseline for our understanding of brain function.

https://www.biac.duke.edu/education/courses/fall04/fmri/readings/week10/2001_NatRevNeuro_Gusnard.pdf

Searching for a baseline: Functional imaging and the resting human brain

The neurohypophysial peptide oxytocin (OT) and OT-like hormones facilitate reproduction in all vertebrates at several levels. The major site of OT gene expression is the magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei. In response to a variety of stimuli such as suckling, parturition, or certain kinds of stress, the processed OT peptide is released from the posterior pituitary into the systemic circulation. Such stimuli also lead to an intranuclear release of OT. Moreover, oxytocinergic neurons display widespread projections throughout the central nervous system. However, OT is also synthesized in peripheral tissues, e.g., uterus, placenta, amnion, corpus luteum, testis, and heart. The OT receptor is a typical class I G protein-coupled receptor that is primarily coupled via Gq proteins to phospholipase C-β. The high-affinity receptor state requires both Mg2+ and cholesterol, which probably function as allosteric modulators. The agonist-binding region of the receptor has bee...

The Oxytocin Receptor System: Structure, Function, and Regulation

http://www.back-in-business-physiotherapy.com/images/files/DescendingControl.pdf

Descending control of pain.

https://www.cell.com/cell/pdf/S0092-8674(02)00722-5.pdf

Coordinated transcription of key pathways in the mouse by the circadian clock.

Vasopressin and oxytocin are made and released by neurons of the hypothalamo-neurohypophysial system. Pulse labeling these neurons with radioactive amino acid indicates that the two hormones and their respective neurophysin carrier proteins are synthesized as parts of separate precursor proteins. The precursors seem to be processed into smaller, biologically active molecules while they are being transported along the axon.

https://science.sciencemag.org/content/sci/207/4429/373.full.pdf

Synthesis, transport, and release of posterior pituitary hormones.

In situ hybridization histochemistry and immunocytochemistry were used to study the prenatal expression of luteinizing hormone-releasing hormone (LHRH) cells in the mouse. Cells expressing LHRH mRNA and peptide product were first detected on embryonic day 11.5 (E11.5) in the olfactory pit. On E12.5, the majority of LHRH cells were located on "tracks" extending from the olfactory pit to the base of the telencephalon. From E12.5 to E15.5, LHRH cells were detected in a rostral-to-caudal gradient in forebrain areas. Prior to E12.5, cells expressing LHRH mRNA were not detected in forebrain areas known to contain LHRH cells in postnatal animals. Quantitation of cells expressing LHRH mRNA showed that the number of labeled cells on E12.5 (approximately 800) equaled the number of LHRH cells in postnatal animals, but more than 90% of these cells were located in nasal regions. Between E12.5 and E15.5, the location of LHRH cells shifted. The number of LHRH cells in the forebrain increased, while the number of LHRH cells in nasal regions decreased over this same period. These findings establish that cells first found in the olfactory pit and thereafter in forebrain areas express the LHRH gene and correspond to the position of LHRH immunopositive cells found at these developmental times. To further examine the ontogeny of the LHRH system, immunocytochemistry in combination with [3H]thymidine autoradiography was used to determine when LHRH cells left the mitotic cycle. We show that LHRH neurons exhibit a discrete time of birth, suggesting that they arise as a single neuronal population between E10.0 and E11.0. Postnatal LHRH neurons were "birth-dated" shortly after differentiation of the olfactory placode and before LHRH mRNA was expressed in cells in the olfactory pit. Taken together, these studies support the hypothesis that all LHRH cells in the central nervous system arise from a discrete group of progenitor cells in the olfactory placode and that a subpopulation of these cells migrate into forebrain areas where they subsequently establish an adult-like distribution.

Evidence that cells expressing luteinizing hormone-releasing hormone mRNA in the mouse are derived from progenitor cells in the olfactory placode

Sokoloff later noted, "This report provides evidence that the increase in glucose utilization evoked by functional activation
 in neural tissue is due to the opening of Na+ channels and activation of Na+, K+ -ATPase activity."

Activity-Dependent Energy Metabolism in Rat Posterior Pituitary Primarily Reflects Sodium Pump Activity

Physiological stimulation of the hypothalamo-neurohypophysial system by salt loading of rats resulted in a dramatically increased glucose utilization in the posterior pituitary but not in the paraventricular or supraoptic nuclei The good correlation between glucose utilization and neural activity in the posterior pituitary (that is, nerve terminals) contrasted with the lack of correlation in the paraventricular and supraoptic nuclei (that is, the sites of the cell bodies of the same neurons) This difference in the metabolic response to functional activity between the two regions of these neurons can be explained by the differences in surface-to-volume ratios of these regions

http://science.sciencemag.org/content/sci/205/4407/723.full.pdf

Metabolic mapping of functional activity in the hypothalamo-neurohypophysial system of the rat

Glucose consumption of the rat suprachiasmatic nuclei (SCN) was studied under various experimental conditions by means of the [14C]deoxyglucose (DG) technique. The results show that glucose consumption of the SCN, in contrast to other brain structures, is a function of both the time of day and environmental lighting conditions. These data are consistent with the hypothesis that the SCN have an essential role in circadian rhythm regulation and indicate that the DG technique may provide a novel approach for the study of the central neural mechanisms underlying circadian rhythm regulation.

https://science.sciencemag.org/content/sci/197/4308/1089.full.pdf

Harold Gainer

Papers

Synthesis, transport, and release of posterior pituitary hormones.

Evidence that cells expressing luteinizing hormone-releasing hormone mRNA in the mouse are derived from progenitor cells in the olfactory placode

Activity-Dependent Energy Metabolism in Rat Posterior Pituitary Primarily Reflects Sodium Pump Activity

Metabolic mapping of functional activity in the hypothalamo-neurohypophysial system of the rat

Suprachiasmatic nucleus: use of 14C-labeled deoxyglucose uptake as a functional marker.