Impairment of DHA synthesis alters the expression of neuronal plasticity markers and the brain inflammatory status in mice

Docosahexaenoic acid (DHA) is a ω-3 fatty acid typically obtained from the diet or endogenously synthesized through the action of elongases (ELOVLs) and desaturases. DHA is a key central nervous system constituent and the precursor of several molecules that regulate the resolution of inflammation. In the present study, we questioned whether the impaired synthesis of DHA affected neural plasticity and inflammatory status in the adult brain. To address this question, we investigated neural and inflammatory markers from mice deficient for ELOVL2 (Elovl2−/−), the key enzyme in DHA synthesis. From our findings, Elovl2−/− mice showed an altered expression of markers involved in synaptic plasticity, learning, and memory formation such as Egr-1, Arc1, and BDNF specifically in the cerebral cortex, impacting behavioral functions only marginally. In parallel, we also found that DHA-deficient mice were characterized by an increased expression of pro-inflammatory molecules, namely TNF, IL-1β, iNOS, caspase-1 as well as the activation and morphologic changes of microglia in the absence of any brain injury or disease. Reintroducing DHA in the diet of Elovl2−/− mice reversed such alterations in brain plasticity and inflammation. Hence, impairment of systemic DHA synthesis can modify the brain inflammatory and neural plasticity status, supporting the view that DHA is an essential fatty acid with an important role in keeping inflammation within its physiologic boundary and in shaping neuronal functions in the central nervous system

Impairment of DHA synthesis alters the expression of neuronal plasticity markers and the brain inflammatory status in mice.

Docosahexaenoic acid (DHA) is a ω-3 fatty acid typically obtained from the diet or endogenously synthesized through the action of elongases (ELOVLs) and desaturases. DHA is a key central nervous system constituent and the precursor of several molecules that regulate the resolution of inflammation. In the present study, we questioned whether the impaired synthesis of DHA affected neural plasticity and inflammatory status in the adult brain. To address this question, we investigated neural and inflammatory markers from mice deficient for ELOVL2 (Elovl2-/- ), the key enzyme in DHA synthesis. From our findings, Elovl2-/- mice showed an altered expression of markers involved in synaptic plasticity, learning, and memory formation such as Egr-1, Arc1, and BDNF specifically in the cerebral cortex, impacting behavioral functions only marginally. In parallel, we also found that DHA-deficient mice were characterized by an increased expression of pro-inflammatory molecules, namely TNF, IL-1β, iNOS, caspase-1 as well as the activation and morphologic changes of microglia in the absence of any brain injury or disease. Reintroducing DHA in the diet of Elovl2-/- mice reversed such alterations in brain plasticity and inflammation. Hence, impairment of systemic DHA synthesis can modify the brain inflammatory and neural plasticity status, supporting the view that DHA is an essential fatty acid with an important role in keeping inflammation within its physiologic boundary and in shaping neuronal functions in the central nervous system

MitoPark mice mirror the slow progression of key symptoms and L-DOPA response in Parkinson's disease

The MitoPark mouse, in which the mitochondrial transcription factor Tfam is selectively removed in midbrain dopamine (DA) neurons, is a genetic model for Parkinson's disease (PD) that replicates the slow and progressive development of key symptoms. To further validate this model, we have extended both behavioral and biochemical analyses in these animals. We found that vertical movements decline earlier and faster than horizontal movements, possibly modeling the early occurrence of axial, postural instability in PD. L-DOPA induces different locomotor responses depending on the age: in young MitoPark mice the L-DOPA-induced motor activation is small; middle-aged MitoPark mice respond in a dose-dependent manner to L-DOPA, whereas aged MitoPark mice display a double-peaked locomotor response to a high dose of L-DOPA that includes an intermittent period of very low motor activity, similar to the 'on-off' phenomenon in PD. To correlate behavior with biochemical data, we analyzed monoamine levels in three different brain areas that are highly innervated by the DA system: striatum, anterior cortex and olfactory bulb. DA levels declined earlier and faster in striatum than in cortex; only at the latest time-point analyzed, DA levels were found to be significantly lower than control levels in the olfactory bulb. Interestingly, the ratio between homovanillic acid (HVA) and DA differed between regions over time. In striatum and olfactory bulb, the ratio increased steeply indicating increased DA turnover. In contrast, the ratio decreased over time in cortex, revealing important differences between DA cells in substantia nigra and the ventral tegmental area

A multicentre study on spontaneous in-cage activity and micro-environmental conditions of IVC housed C57BL/6J mice during consecutive cycles of bi-weekly cage-change.

Mice respond to a cage change (CC) with altered activity, disrupted sleep and increased anxiety. A bi-weekly cage change is, therefore, preferred over a shorter CC interval and is currently the prevailing routine for Individually ventilated cages (IVCs). However, the build-up of ammonia (NH3) during this period is a potential threat to the animal health and the literature holds conflicting reports leaving this issue unresolved. We have therefor examined longitudinally in-cage activity, animal health and the build-up of ammonia across the cage floor with female and male C57BL/6 mice housed four per IVC changed every other week. We used a multicentre design with a standardised husbandry enabling us to tease-out features that replicated across sites from those that were site-specific. CC induce a marked increase in activity, especially during daytime (~50%) when the animals rest. A reduction in density from four to two mice did not alter this response. This burst was followed by a gradual decrease till the next cage change. Female but not male mice preferred to have the latrine in the front of the cage. Male mice allocate more of the activity to the latrine free part of the cage floor already the day after a CC. A behaviour that progressed through the CC cycle but was not impacted by the type of bedding used. Reducing housing density to two mice abolished this behaviour. Female mice used the entire cage floor the first week while during the second week activity in the latrine area decreased. Measurement of NH3 ppm across the cage floor revealed x3 higher values for the latrine area compared with the opposite area. NH3 ppm increases from 0-1 ppm to reach ≤25 ppm in the latrine free area and 50-100 ppm in the latrine area at the end of a cycle. As expected in-cage bacterial load covaried with in-cage NH3 ppm. Histopathological analysis revealed no changes to the upper airways covarying with recorded NH3 ppm or bacterial load. We conclude that housing of four (or equivalent biomass) C57BL/6J mice for 10 weeks under the described conditions does not cause any overt discomfort to the animals

High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio

At present, there are few means to track symptomatic stages of CNS aging. Thus, although metabolic changes are implicated in mtDNA mutation-driven aging, the manifestations remain unclear. Here, we used normally aging and prematurely aging mtDNA mutator mice to establish a molecular link between mitochondrial dysfunction and abnormal metabolism in the aging process. Using proton magnetic resonance spectroscopy and HPLC, we found that brain lactate levels were increased twofold in both normally and prematurely aging mice during aging. To correlate the striking increase in lactate with tissue pathology, we investigated the respiratory chain enzymes and detected mitochondrial failure in key brain areas from both normally and prematurely aging mice. We used in situ hybridization to show that increased brain lactate levels were caused by a shift in transcriptional activities of the lactate dehydrogenases to promote pyruvate to lactate conversion. Separation of the five tetrameric lactate dehydrogenase (LDH) isoenzymes revealed an increase of those dominated by the Ldh-A product and a decrease of those rich in the Ldh-B product, which, in turn, increases pyruvate to lactate conversion. Spectrophotometric assays measuring LDH activity from the pyruvate and lactate sides of the reaction showed a higher pyruvate → lactate activity in the brain. We argue for the use of lactate proton magnetic resonance spectroscopy as a noninvasive strategy for monitoring this hallmark of the aging process. The mtDNA mutator mouse allows us to conclude that the increased LDH-A/LDH-B ratio causes high brain lactate levels, which, in turn, are predictive of aging phenotypes

Sickness absence and concurrent low back and neck–shoulder pain: results from the MUSIC-Norrtälje study

In Sweden, musculoskeletal disorders, in particular low back disorders (LBD) and neck–shoulder disorders (NSD) constitute by far the most common disorders, causing sick leave and early retirement. Studies that compare sickness absence in individuals with LBD and individuals with NSD are lacking. Moreover, it is likely that having concurrent complaints from the low back region and the neck–shoulder region could influence sickness absence. The purpose of the present study was to explore potential differences in sickness absence and in long-term sickness absence during a 5-year period, 1995–2001, among individuals with (1) solely LBD, (2) solely NSD, and (3) concurrent LBD and NSD. The present study was based on 817 subjects from the MUSIC-Norrtälje study, whom were working at baseline and whom at both baseline and follow-up reported LBD and/or NSD. Three groups were identified based on pain and pain-related disability at both baseline and follow-up: (1) solely LBD, (2) solely NSD, and (3) concurrent LBD and NSD. Subjects who did not give consistent answers at both the baseline and follow-up occasions were assigned a fourth group: (4) migrating LBD/NSD. Two outcomes were analysed: (1) prevalence of sickness absence, and (2) long-term sickness absence among those with sickness absence days. Logistic regression analysis was used to calculate odds ratios (OR) for sickness absence in the different disorder groups, taking into account confounding factors such as gender, age and other non-musculoskeletal-related disorders. In the group concurrent LBD and NSD, 59% had been sickness absent between baseline and follow up, compared to 42% in the group solely LBD, 41% in the group solely NSD, and 46% in the group migrating LBD/NSD. No difference in sickness absence was found between the group solely LBD compared to the group solely NSD [OR 0.65 (0.36–1.17)]. The adjusted OR for sickness absence in the group concurrent LBD and NSD compared to subjects with solely LBD or solely NSD was [OR 1.69 (1.14–2.51)]. The adjusted OR for having long-term sickness absence was 2.48 (95% CI = 1.32–4.66) for the group concurrent LBD and NSD. In the present study, having concurrent LBD and NSD were associated with a higher risk for sickness absence and also long-term sickness absence. This suggests that, when research on sickness absence and return to work after a period of LBD or NSD is performed, it is important to take into consideration any concurrent pain from the other spinal region. The study also implies that spinal co-morbidity is an important factor to be considered by clinicians and occupational health providers in planning treatment, or in prevention of these disorders

The influence of work-related exposures on the prognosis of neck/shoulder pain

To determine associations between work-related exposures and the prognosis of self-reported neck/shoulder pain. This prospective cohort study was based on 803 working subjects who reported neck/shoulder pain at baseline. The proportion of subjects who 5–6 years later were symptom-free was calculated. Data concerning work-related biomechanical, psychosocial, and organizational exposures were collected at baseline. The Cox regression analyses were used to calculate the relative chances (RC) of being symptom-free at the end of the study for single exposures, and also for up to three simultaneous work-related exposures. Adjustments were made for sex and age. Only 36% of the subjects were symptom-free 5–6 years later. The relative chance for being symptom-free at the end of the study was 1.32 (95% CI = 0.99–1.74) for subjects who were exposed to sitting ≥75% of the working time and 1.53 (95% CI = 1.02–2.29) for subjects who were exposed to job strain, i.e., the combination of high demands and low decision latitude. The relative chance of being symptom-free at the end of the study was 0.61 (95% CI = 0.40–0.94) for subjects with at least two out of three simultaneous biomechanical exposures at work; manual handling, working with the hands above shoulder level, and working with vibrating tools. In a heterogeneous population with moderate nonspecific neck/shoulder pain, sedentary work enhanced the chance of being symptom-free 5–6 years later, whereas simultaneous exposures to at least two of manual handling, working with hands above shoulder level and working with vibrating tools were associated with a lower chance of being symptom-free at the end of the study. This could imply that subjects with neck/shoulder pain should avoid such simultaneous exposures