A dopaminergic switch for fear to safety transitions

Overcoming aversive emotional memories requires neural systems that detect when fear responses are no longer appropriate so that they can be extinguished. The midbrain ventral tegmental area (VTA) dopamine system has been implicated in reward and more broadly in signaling when a better-than-expected outcome has occurred. This suggests that it may be important in guiding fear to safety transitions. We report that when an expected aversive outcome does not occur, activity in midbrain dopamine neurons is necessary to extinguish behavioral fear responses and engage molecular signaling events in extinction learning circuits. Furthermore, a specific dopamine projection to the nucleus accumbens medial shell is partially responsible for this effect. In contrast, a separate dopamine projection to the medial prefrontal cortex opposes extinction learning. This demonstrates a novel function for the canonical VTA-dopamine reward system and reveals opposing behavioral roles for different dopamine neuron projections in fear extinction learning

Serotonergic treatment normalizes midbrain dopaminergic neuron increase after periaqueductal gray stimulation-induced anticipatory fear in a rat mode

Background: Electrical stimulation of the dorsolateral periaqueductal gray (dlPAG) in rats has been shown to elicit panic-like behaviour and can be a useful tool for modelling anticipatory fear and agoraphobia. Methods: In this study, we further analysed our previous data on the effects of escitalopram (a selective serotonin reuptake inhibitor, SSRI) and buspirone (a 5-HT1A receptor partial agonist) on dlPAG-induced anticipatory fear behaviour in a rat model using freezing as a measure. We then used tyrosine hydroxylase (TH) immunohistochemistry to probe the effects on dopaminergic neurons. Results: Although acute treatment of escitalopram, but not buspirone, was effective in reducing anticipatory freezing behaviour, chronic administrations of both drugs were comparably effective. We found that the number of dopaminergic neurons in the ventral tegmental area (VTA) was lowered in both chronic buspirone and escitalopram groups. We showed a strong correlation between the number of dopaminergic neurons and freezing in the VTA. We further showed positive correlations between dopaminergic neurons in the VTA and substantia nigra pars compacta in escitalopram and buspirone groups, respectively. Limitations: Although our data strongly hint to a role of dopaminergic mechanisms in the dlPAG induced fear response, more in-depth studies with larger sample sizes are needed to understand the neuronal mechanisms underlying the interactions between serotonergic drugs and dopaminergic cell number and fear behavior. Conclusion: Chronic treatment with an SSRI and a 5-HT1A agonist decrease the number of dopaminergic neurons in the VTA. These effects seem to be associated with reduced dlPAG-induced anticipatory freezing behaviour

Ginseng and ginkgo biloba effects on cognition as modulated by cardiovascular reactivity: a randomised trial

Background There is some evidence to suggest that ginseng and Ginkgo biloba can improve cognitive performance, however, very little is known about the mechanisms associated with such improvement. Here, we tested whether cardiovascular reactivity to a task is associated with cognitive improvement. Methodology/Principal findings Using a double-blind, placebo controlled, crossover design, participants (N = 24) received two doses of Panax Ginseng (500, 1000 mg) or Ginkgo Biloba (120, 240 mg) (N = 24), and underwent a series of cognitive tests while systolic, diastolic, and heart rate readings were taken. Ginkgo Biloba improved aspects of executive functioning (Stroop and Berg tasks) in females but not in males. Ginseng had no effect on cognition. Ginkgo biloba in females reversed the initial (i.e. placebo) increase in cardiovascular reactivity (systolic and diastolic readings increased compared to baseline) to cognitive tasks. This effect (reversal) was most notable after those tasks (Stroop and Iowa) that elicited the greatest cardiovascular reactivity during placebo. In males, although ginkgo also decreased cardiovascular readings, it did so from an initial (placebo) blunted response (i.e. decrease or no change from baseline) to cognitive tasks. Ginseng, on the contrary, increased cardiovascular readings compared to placebo. Conclusions/Significance These results suggest that cardiovascular reactivity may be a mechanism by which ginkgo but not ginseng, in females is associated with certain forms of cognitive improvement

Tyrosine negatively affects flexible-like behaviour under cognitively demanding conditions

Background The catecholaminergic precursor to dopamine, tyrosine, is an important modulator of cognitive performance. A number of studies have demonstrated that the beneficial effects of tyrosine on cognitive performance are most pronounced when individuals are exposed to stressful situations, such as hypothermia. However, little is known about whether manipulation of stress using non-aversive stimuli, such as cognitive demand, can also bring about similar improvements. Methods We conducted a randomized, double-blind, placebo-controlled experiment to test the effects of tyrosine administration and cognitive load (low or high) on cognitive flexibility, a measure known to be influenced by catecholaminergic function. A total of 70 healthy volunteers completed a baseline cognitive flexibility test (Wisconsin Card Sorting Test: WCST). Participants were given a dose of either tyrosine (2.0 g) or placebo (cellulose) and subject to either low cognitive load (simple reaction time task) or high cognitive load (digit memory span task), immediately followed by a WCST for a second time. Results Contrary to expectations, we found that instead of ameliorating performance under the high cognitive load condition, tyrosine worsened cognitive flexibility. Limitations Physiological marker of stress was not measured. Conclusions Our results suggest that aversive stressors and cognitive demand modulate the effects of tyrosine on cognitive performance in a differential manner

How have COVID‐19 stringency measures changed scholarly activity?

Government restrictions to the movement of people due to the COVID-19 pandemic have had a wide range of effects on scientific activity. Here, we show that during the pandemic there has been a reduction in the number of registered non-COVID-19 clinical trials. Furthermore, using the Oxford COVID-19 Government Response Tracker Stringency Index (SI) as an indicator of COVID-19–related workplace adjustment (e.g., restrictions on gatherings, workplace closures, and stay-at-home orders), we demonstrate that this drop in clinical trial registration has been greater in countries with a higher SI. This could have significant consequences for the discovery of treatments that are required to reduce the global burden of disease

How have COVID-19 stringency measures changed scholarly activity?

Government restrictions to the movement of people due to the COVID-19 pandemic have resulted in a reduction in the number of registered non COVID-19 clinical trials which was in turn negatively correlated with the stringency index of a country. This could have serious consequences for the discovery of treatments that are required to reduce the global burden of disease (GBD)

The effect of anti-IgE therapy in knee osteoarthritis: a pilot observational study.

Osteoarthritis is a whole-joint disease and its pathogenesis remains poorly understood. Recent evidence proposed the importance of the innate immune system as trigger of synovium inflammation following the degeneration of cartilage. Moreover, synovial mast cells (MCs) might be correlated with pain and disability reported by patients. Anti IgE therapy represents a new class of MCs stabilizing agent, licensed for people with asthma and chronic urticaria. Therefore, we studied if the stabilizing effect of anti IgE would improve the pain and disability in patients affected by knee osteoarthritis and atopic disease. This pilot study provides the first evidence that anti IgE treatment induces a short-term clinical improvement supporting the role of MCs in osteoarthritis

Homologous platelet-rich plasma for the treatment of knee involvement in primary Sjögren\u92s syndrome.

Primary Sjögren\u92s syndrome (pSS) is a chronic autoimmune disease characterized by dry eyes, dry mouth, and other clinical manifestations. The most common extraglandular manifestation of pSS is articular involvement and to date their management is unclear. The aims of the current pilot study were to assess the safety and the outcomes of homologous platelet-rich plasma (HPRP) injections in pSS cohort affected by knee arthralgia/arthritis at short-term follow up. This pilot study provides the first evidence that HPRP injections are a safe treatment and induce a short-term clinical improvement. Although the lack of a control group, randomization and long-term follow up prevents the assessment of the real effectiveness of this treatment, further studies are needed to confirm these findings and to determine the mechanism of action, biological changes and disease-modifying properties of PRP

Genipin-crosslinked chitosan gels and scaffolds for tissue engineering and regeneration of cartilage and bone

The present review article intends to direct attention to the technological advances made since 2009 in the area of genipin-crosslinked chitosan (GEN-chitosan) hydrogels. After a concise introduction on the well recognized characteristics of medical grade chitosan and food grade genipin, the properties of GEN-chitosan obtained with a safe, spontaneous and irreversible chemical reaction, and the quality assessment of the gels are reviewed. The antibacterial activity of GEN-chitosan has been well assessed in the treatment of gastric infections supported by Helicobacter pylori. Therapies based on chitosan alginate crosslinked with genipin include stem cell transplantation, and development of contraction free biomaterials suitable for cartilage engineering. Collagen, gelatin and other proteins have been associated to said hydrogels in view of the regeneration of the cartilage. Viability and proliferation of fibroblasts were impressively enhanced upon addition of poly-l-lysine. The modulation of the osteocytes has been achieved in various ways by applying advanced technologies such as 3D-plotting and electrospinning of biomimetic scaffolds, with optional addition of nano hydroxyapatite to the formulations. A wealth of biotechnological advances and know-how has permitted reaching outstanding results in crucial areas such as cranio-facial surgery, orthopedics and dentistry. It is mandatory to use scaffolds fully characterized in terms of porosity, pore size, swelling, wettability, compressive strength, and degree of acetylation, if the osteogenic differentiation of human mesenchymal stem cells is sought: in fact, the novel characteristics imparted by GEN-chitosan must be simultaneously of physico-chemical and cytological nature. Owing to their high standard, the scientific publications dated 2010-2015 have met the expectations of an interdisciplinary audience