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.

/pdf/hypothetical-model-of-dynamic-biomarkers-of-the-alzheimer-s-5azt2w7laa.pdf

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.

The patterns of protein metabolism of identified cholinergic (R2, L10, and L11) and neurosecretory (R3–13, R14, and Bag cells) cells were analyzed with the use of SDS-polyacrylamide gel electrophoresis and isoelectric focusing. L11 was unique amongst the three cholinergic neurons in its relatively high rate of incorporation of labeled leucine into proteins at 12,000 daltons. All the neurosecretory cells incorporated relatively large quantities of 3H-leucine into small proteins (<12,000 daltons), which were concentrated in putative neurosecretory granule fractions of these cells. R3–13 and R14 synthesized a distinct basic protein which appeared specifically in the branchial nerve which contains the axons of these cells. The combination of these two analytical electrophoretic techniques allowed for the characterization of protein specificity in single nerve cells.

Specific protein metabolism in identifiable neurons of Aplysia californica

Studies on bursting pacemaker potential activity in molluscan neurons. II. Regulation by divalent cations

Five serially sectioned tissue slices (400 microns) from the preoptic area/hypothalamus of postnatal day 4 rats were cultured using a slice explant roller culture technique. After 18 days in culture, these slices thinned sufficiently to allow immunocytochemical and in situ hybridization histochemical assays for LHRH peptide and LHRH mRNA, respectively. Large numbers of neurons containing mRNA encoding LHRH were detected in these slices using in situ hybridization histochemistry (ISHH). These 35S-labeled cells were distributed in the cultured slices in a pattern similar to that found with LHRH immunocytochemistry and ISHH in vivo, indicating that LHRH neurons were maintained in these cultures in an organotypic manner. Densitometric single cell analyses after ISHH of the culture slices were performed using a Loats image analysis system, so as to provide a density value per cell (density/cell). Comparisons of these density values from the slice explants cultured in presence or absence of 10(-7) M estradiol found that: 1) under basal (control) culture conditions there were no consistent differences in the frequency distributions of the density/cell values between all the five slices derived from either male or female rats, 2) mean density/culture values under control conditions did not differ significantly between slices and sexes, 3) the presence of estradiol in the culture media resulted in an overall decrease in density/cell values, with the most significant decrease occurring in slice 3 which is comparable to the level of the organum vasculosum lamina terminalis/rostral preoptic area (OVLT/rPOA) in vivo, and 4) this decrease in density/cell values in slice 3 due to estradiol treatment, was greater in cultures derived from female vs. male tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

/pdf/differential-effects-of-estrogen-on-luteinizing-hormone-3utnjvtf9y.pdf

Differential Effects of Estrogen on Luteinizing Hormone-Releasing Hormone Gene Expression in Slice Explant Cultures Prepared from Specific Rat Forebrain Regions

Low molecular weight specific proteins in identified molluscan neurons. I. Synthesis and storage

Rat and mouse hypothalami from postnatal animals containing highly differentiated neurones survive very well in long-term (>15 days in vitro, DIV) stationary organotypic cultures. Magnocellular oxytocin (OT) and vasopressin (VP) neurones are present in identifiable paraventricular (PVN), supraoptic (SON) and accessory (ACC) nuclei in these cultures. After 15 DIV in standard medium immunocytochemistry revealed 427 +/- 63 OT cells and 217 +/- 27 VP cells per cultured rat hypothalamus, and 380 +/- 72 OT cells and 622 +/- 91 VP cells per cultured mouse hypothalamus. Following a 7-day adaptation period in standard culture medium containing serum, the rat slice-explants survived very well after subsequent transfer to defined, serum- free media (SFM) for an additional 8 days. The number of OT cells surviving in SFM was 612 +/- 147 OT cells per cultured rat hypothalamus. Only 0.5% of the magnocellular OT and VP neurones in the cultures appeared to express both peptides. Experiments on c-fos gene expression in these cultures showed that while only 12% of the magnocellular OT and VP neurones contained barely detectable Fos protein in their nuclei under control conditions, potassium depolarization of these cultures for 3 h produced intense c-fos expression in 87-91% of these cells. Thus, magnocellular neurones in these cultures are sufficiently stable and responsive to permit long-term physiological and gene expression studies to be done under defined media conditions.

Harold Gainer

Papers

Specific protein metabolism in identifiable neurons of Aplysia californica

Studies on bursting pacemaker potential activity in molluscan neurons. II. Regulation by divalent cations

Differential Effects of Estrogen on Luteinizing Hormone-Releasing Hormone Gene Expression in Slice Explant Cultures Prepared from Specific Rat Forebrain Regions

Low molecular weight specific proteins in identified molluscan neurons. I. Synthesis and storage

Stationary organotypic cultures of oxytocin and vasopressin magnocellular neurones from rat and mouse hypothalamus.