Blocking human fear memory with the matrix metalloproteinase inhibitor doxycycline

Learning to predict threat is a fundamental ability of many biological organisms, and a laboratory model for anxiety disorders. Interfering with such memories in humans would be of high clinical relevance. On the basis of studies in cell cultures and slice preparations, it is hypothesised that synaptic remodelling required for threat learning involves the extracellular enzyme matrix metalloproteinase (MMP) 9. However, in vivo evidence for this proposal is lacking. Here we investigate human Pavlovian fear conditioning under the blood-brain barrier crossing MMP inhibitor doxycyline in a pre-registered, randomised, double-blind, placebo-controlled trial. We find that recall of threat memory, measured with fear-potentiated startle 7 days after acquisition, is attenuated by ~60% in individuals who were under doxycycline during acquisition. This threat memory impairment is also reflected in increased behavioural surprise signals to the conditioned stimulus during subsequent re-learning, and already late during initial acquisition. Our findings support an emerging view that extracellular signalling pathways are crucially required for threat memory formation. Furthermore, they suggest novel pharmacological methods for primary prevention and treatment of posttraumatic stress disorder.Molecular Psychiatry advance online publication, 4 April 2017; doi:10.1038/mp.2017.65

A practical application of photogrammetry to performing rib characterization measurements in an underground coal mine using a DSLR camera

Understanding coal mine rib behavior is important for inferring pillar loading conditions as well as ensuring the safety of miners who are regularly exposed to ribs. Due to the variability in the geometry of underground openings and ground behavior, point measurements often fail to capture the true movement of mine workings. Photogrammetry is a potentially fast, cheap, and precise supplemental measurement tool in comparison to extensometers, tape measures, or laser range meters, but its application in underground coal has been limited. The practical use of photogrammetry was tested at the Safety Research Coal Mine, National Institute for Occupational Safety and Health (NIOSH). A commercially available, digital single-lens reflex (DSLR) camera was used to perform the photogrammetric surveys for the experiment. Several experiments were performed using different lighting conditions, distances to subject, camera settings, and photograph overlaps, with results summarized as follows: the lighting method was found to be insignificant if the scene was appropriately illuminated. It was found that the distance to the subject has a minimal impact on result accuracy, and that camera settings have a significant impact on the photogrammetric quality of images. An increasing photograph resolution was preferable when measuring plane orientations; otherwise a high point cloud density would likely be excessive. Focal ratio (F-stop) changes affect the depth of field and image quality in situations where multiple angles are necessary to survey cleat orientations. Photograph overlap is very important to proper three-dimensional reconstruction, and at least 60% overlap between photograph pairs is ideal to avoid unnecessary post-processing. The suggestions and guidelines proposed are designed to increase the quality of photogrammetry inputs and outputs as well as minimize processing time, and serve as a starting point for an underground coal photogrammetry study. Keywords: Photogrammetry, Coal mining, Underground, Rib characterizatio

Caught in the Net: Perineuronal Nets and Addiction

Exposure to drugs of abuse induces plasticity in the brain and creates persistent drug-related memories. These changes in plasticity and persistent drug memories are believed to produce aberrant motivation and reinforcement contributing to addiction. Most studies have explored the effect drugs of abuse have on pre- and postsynaptic cells and astrocytes; however, more recently, attention has shifted to explore the effect these drugs have on the extracellular matrix (ECM). Within the ECM are unique structures arranged in a net-like manner, surrounding a subset of neurons called perineuronal nets (PNNs). This review focuses on drug-induced changes in PNNs, the molecules that regulate PNNs, and the expression of PNNs within brain circuitry mediating motivation, reward, and reinforcement as it pertains to addiction

Consumption of a High-Fat Diet Alters Perineuronal Nets in the Prefrontal Cortex

A key factor in the development of obesity is the overconsumption of fatty foods, which, in addition to facilitating weight gain, alters neuronal structures within brain reward circuitry. Our previous work demonstrates that sustained consumption of a high-fat diet (HFD) attenuates spine density in the prefrontal cortex (PFC). Whether HFD promotes structural adaptation among inhibitory cells of the PFC is presently unknown. One structure of interest is the perineuronal net (PNN), a specialized extracellular matrix surrounding, primarily, parvalbumin-containing GABAergic interneurons. PNNs contribute to synaptic stabilization, protect against oxidative stress, regulate the ionic microenvironment within cells, and modulate regional excitatory output. To examine diet-induced changes in PNNs, we maintained rats on one of three dietary conditions for 21 days: ad libitum chow, ad libitum 60% high fat (HF-AL), or limited-access calorically matched high fat (HF-CM), which produced no significant change in weight gain or adiposity with respect to chow controls. The PNN “number” and intensity were then quantified in the prelimbic (PL-PFC), infralimbic (IL-PFC), and ventral orbitofrontal cortex (OFC) using Wisteria floribunda agglutinin (WFA). Our results demonstrated that fat exposure, independent of weight gain, induced a robust decrease in the PNN intensity in the PL-PFC and OFC and a decrease in the PNN number in the OFC

Consumption of a High-Fat Diet Alters Perineuronal Nets in the Prefrontal Cortex

A key factor in the development of obesity is the overconsumption of fatty foods, which, in addition to facilitating weight gain, alters neuronal structures within brain reward circuitry. Our previous work demonstrates that sustained consumption of a high-fat diet (HFD) attenuates spine density in the prefrontal cortex (PFC). Whether HFD promotes structural adaptation among inhibitory cells of the PFC is presently unknown. One structure of interest is the perineuronal net (PNN), a specialized extracellular matrix surrounding, primarily, parvalbumin-containing GABAergic interneurons. PNNs contribute to synaptic stabilization, protect against oxidative stress, regulate the ionic microenvironment within cells, and modulate regional excitatory output. To examine diet-induced changes in PNNs, we maintained rats on one of three dietary conditions for 21 days: ad libitum chow, ad libitum 60% high fat (HF-AL), or limited-access calorically matched high fat (HF-CM), which produced no significant change in weight gain or adiposity with respect to chow controls. The PNN “number” and intensity were then quantified in the prelimbic (PL-PFC), infralimbic (IL-PFC), and ventral orbitofrontal cortex (OFC) using Wisteria floribunda agglutinin (WFA). Our results demonstrated that fat exposure, independent of weight gain, induced a robust decrease in the PNN intensity in the PL-PFC and OFC and a decrease in the PNN number in the OFC

Over-the-Counter Medications in Cardiac Transplant Recipients: Guidelines for Use

OBJECTIVE: The purpose of this article is to review the pathophysiology of the denervated heart and the factors that need to be considered before recommending the use of over-the-counter (OTC) medications in the cardiac transplant recipient. DATA SOURCES: Pharmacology and therapeutic textbooks, English-language journal articles, and physiology textbooks published between 1969 and 1991. DATA EXTRACTION: Case reports, controlled case studies, and textbook chapters evaluating drug interactions with immunosuppressive agents were reviewed. The effects of various OTC medications on the denervated heart were examined and relevant material was extrapolated. DATA ANALYSIS: The number of cases or studies in which a particular effect or interaction occurred was reported. Those findings that were less well documented were either identified as such or were not included in the review. DATA SYNTHESIS: Common pharmacokinetic and pharmacodynamic interactions with the primary immunosuppressive agents (e.g., cyclosporine, azathioprine, prednisone) are reviewed. The physiology and altered responses of the denervated heart to various medications are also explained. Using this information, recommendations are given for the use and monitoring of OTC analgesics, antacids, laxatives, sleep aids, stimulants, and other medications that may be used in the cardiac transplant recipient. CONCLUSIONS: Many OTC medications can be used safely in the cardiac transplant recipient. In each situation, risk/benefit assessments must always be made and therapy should be monitored closely. Most important, patients should always notify the transplant team before adding an OTC product to their immunosuppressive regimen. </jats:sec

Cocaine exposure modulates perineuronal nets and synaptic excitability of fast-spiking interneurons in the medial prefrontal cortex

eNeuro, 5, 1–17Note : if this item contains full text it may be a preprint, author manuscript, or a Gold OA copy that permits redistribution with a license such as CC BY. The final version is available through the publisher’s platform.We previously reported that perineuronal nets (PNNs) are required for cocaine-associated memories. Perineuronal nets are extracellular matrix that primarily surrounds parvalbumin (PV)-containing, GABAergic fast-spiking interneurons (FSIs) in the medial prefrontal cortex (mPFC). Here we measured the impact of acute (1 d) or repeated (5 d) cocaine exposure on PNNs and PV cells within the prelimbic and infralimbic regions of the mPFC. Adult rats were exposed to 1 or 5 d of cocaine and stained for PNNs (using Wisteria floribunda agglutinin) and PV intensity 2 or 24 h later. In the prelimbic and infralimbic PFC, PNN staining intensity decreased 2 h after 1 d of cocaine exposure but increased after 5 d of cocaine exposure. Cocaine also produced changes in PV intensity, which generally lagged behind that of PNNs. In the prelimbic PFC, both 1 and 5 d of cocaine exposure increased GAD65/67 puncta near PNN-surrounded PV cells, with an increase in the GAD65/67-to-VGluT1 puncta ratio after 5 d of cocaine exposure. In the prelimbic PFC, slice electrophysiology studies in FSIs surrounded by PNNs revealed that both 1 and 5 d of cocaine exposure reduced the number of action potentials 2 h later. Synaptic changes demonstrated that 5 d of cocaine exposure increased the inhibition of FSIs, potentially reducing the inhibition of pyramidal neurons and contributing to their hyperexcitability during relapse behavior. These early and rapid responses to cocaine may alter the network stability of PV FSIs that partially mediate the persistent and chronic nature of drug addiction.National Institute on Drug Abus