Using a combination of anterograde and retrograde neuronal tract-tracing techniques, the descending projections from the paraventricular nucleus of the hypothalamus (PVN) to the brain/spinal cord and in particular those axonal projections that appear to be contiguous with sympathetic preganglionic neurones (SPN) projecting to the stellate ganglion have been studied. Descending PVN pathways were located by the anterograde transport of biotinylated dextran amine (BDA), whilst SPN were retrogradely labelled with cholera B toxin subunit conjugated to horseradish peroxidase (CB-HRP). BDA-labelled PVN axons terminated in both hypothalamic and extrahypothalamic (including the midbrain, medulla and spinal cord) brain nuclei, with dense terminal labelling observed particularly in the arcuate hypothalamic nucleus and adjacent median eminence, in the solitary tract, vagal nuclei and in the intermediolateral region of the spinal cord (IML). Varicose descending PVN fibres in the IML were often observed to closely appose both the cell soma and dendrites of retrogradely labelled SPN (projecting to the stellate ganglion) in the spinal cord. In addition, it was shown that PVN descending axons crossing to the contralateral side of the spinal cord were closely associated with retrogradely labelled SPN projecting to the superior cervical ganglion. Such findings suggest that descending pathways from the PVN may exhibit a direct influence on cardiac sympathetic outflow and may also influence the behaviour of the contralateral population of SPN projecting to the superior cervical ganglion.

BACKGROUND Age-associated myenteric neuronal loss has been described in several species. In some studies,cholinergic neurons have been reported to be selectively vulnerable, whereas nitrergic neurons are spared. Aging of the mouse enteric nervous system(ENS) and the subtypes of mouse myenteric neurons that may be lost have been little studied. We therefore investigated changes in the numbers of total neurons and two neuronal subpopulations in the mouse distal colon during aging. METHODS Wholemount preparations from 3–4-, 12–13-, 18–19-, and 24–25-month-old C57BL/6 mice were double immunolabeled with HuC/D antibody to identify the total neuronal population and antisera to either calbindin or neuronal nitric oxide synthase (nNOS) to identify myenteric neuronal subpopulations. Samples were analyzed by confocal microscopy. New procedures were employed to ensure unbiased counting and to correct for changes in gut dimensions with age and stretch during sample preparation. The density of nerve fibers in the tertiary plexus was also studied. KEY RESULTS No significant change in numbers of total neurons or of either subpopulation with age was measured, but because of gut growth, the density of myenteric neurons decreased between 3–4 and 12–13 months. The density of nNOS-immunoreactive nerve fibers in the tertiary plexus increased significantly with age, up to 18–19 months. Numerous swollen processes of CB and nNOS-immunoreactive neurons were observed in 18–19- and 24–25-month-old animals. Conclusions &Inferences These results indicate that aging does not result in a loss of myenteric neurons in mouse distal colon at the ages studied, although neurodegenerative changes, which may impact on neuronal function, do occur.

The influence of isotopically enriched magnesium on the creatine kinase catalyzed phosphorylation of adenosine diphosphate is examined in two independent series of experiments where adenosine triphosphate (ATP) concentrations were determined by a luciferase-linked luminescence end-point assay or a real-time spectrophotometric assay. No increase was observed between the rates of ATP production with natural Mg, 24 Mg, and 25 Mg, nor was any significant magnetic field effect observed in magnetic fields from 3 to 1,000 mT. Our results are in conflict with those reported by Buchachenko et al. [J Am Chem Soc 130:12868–12869 (2008)], and they challenge these authors’ general claims that a large (two- to threefold) magnetic isotope effect is “universally observable” for ATP-producing enzymes [Her Russ Acad Sci 80:22–28 (2010)] and that “enzymatic phosphorylation is an ion-radical, electron-spin-selective process” [Proc Natl Acad Sci USA 101:10793–10796 (2005)].

A recent study using transsynaptically transported pseudorabies virus, injected into the adrenal gland, showed labelled neurones in the paraventricular nucleus (PVN) of the hypothalamus, indicating that these neurones send projections to sympathoadrenal preganglionic neurones (SPNs). However, this technique cannot conclusively demonstrate that the pathway is monosynaptic. In order to investigate the possibility of a direct projection from the PVN to SPNs, the present study used the anterograde tracer biotin dextran amine to label paraventricular spinal projections and the retrograde tracer cholera toxin B conjugated to horseradish peroxidase to label SPNs. In addition, because electrophysiological evidence suggests vasopressin to be a neurotransmitter candidate in this pathway, immunocytochemical identification of the peptide and retrograde labelling of SPNs to the adrenal medulla were used to investigate this. The results of these studies show spinally projecting paraventricular axons with terminal varicosities closely associated with SPNs. Therefore some of these associations may represent boutons forming synaptic contact on SPNs. Similarly, vasopressin fibres were found close to the dendrites and soma of SPNs. It is suggested that spinal axons originating from paraventricular neurones can provide a direct influence on adrenal medullary function, that vasopressin is a possible neurotransmitter involved in some of these connections and this is one means by which the paraventricular nucleus can generate a defence to stressful stimuli.

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A preliminary study was undertaken to provide clinical evidence to support the hypothesis that: "Migraine with aura, migraine without aura and aura alone are the same condition, which differ in degree rather than pathophysiology." At the City of London Migraine Clinic, 50 patients consecutively attending the clinic with a past or present history of migraine with aura were questioned. Of the 50 patients questioned 36 (70%) had a combination of migraine with aura, migraine without aura and/or aura alone; i.e. 70% had had more than one type of migraine attack. The duration, severity and frequency of attacks did not differ between migraine with and migraine without aura. Conclusion--the results support the hypothesis that migraine with and migraine without aura, and aura alone are not separate conditions, because: (1) most patients suffer from more than one type of migraine attack; (2) there are no significant differences in the characteristics of the migraine attacks in the different groups; (3) there are no significant differences in the characteristics of the subjects.

Treatment for chronic constipation in older people is challenging and the condition has a major impact on quality of life. A lack of understanding about the causes of this condition has hampered the development of effective treatments. 5-HT is an important pro-kinetic agent in the colon. We examined whether alterations in colonic 5-HT signalling underlie age–related changes in faecal output in mice and whether these changes were due to an increase in TNF-α. Components of the 5-HT signalling system (5-HT, 5-HIAA, SERT) and TNF-α expression were examined in the distal colon of 3, 12, 18 and 24-month old mice and faecal output and water content monitored under control conditions and following the administration of etanercept (TNF-α inhibitor; 1 mg Kg−1). Faecal output and water content were reduced in aged animals. Age increased mucosal 5-HT availability and TNF-α expression and decreased mucosal SERT expression and 5-HIAA. Etanercept treatment of old mice reversed these changes, suggesting that age-related changes in TNFα expression are an important regulator of mucosal 5-HT signalling and pellet output and water content in old mice. These data point to “anti-TNFα” drugs as potential treatments for age-related chronic constipation.

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