Dopamine regulation of contextual fear and associated neural circuit function

© 2020 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd Learning to associate certain contexts with threat and adapting to changing environmental contingencies by learning that such contexts are no longer associated with threat are both crucial for survival. Research over the last few decades has made considerable progress in determining the brain areas involved in the encoding, retrieval and extinction of contextual fear. These studies have identified the hippocampus and amygdala, along with the prefrontal cortex and other inter-connected brain areas, as key players in contextual fear processing. In contrast to the neural circuit basis of contextual fear, the neurochemical mechanisms involved in its regulation remain poorly understood. Dopamine is well known for its role in appetitive learning but this neurotransmitter is also important for other types of learning, including spatial and aversive memory processing. Dopamine is ideally positioned to regulate contextual fear given that the areas involved receive dopamine input and express dopamine receptors. Moreover, neuronal activity, functional connectivity and synaptic plasticity in this neural circuitry are modulated by dopamine receptor signalling. Here, we review the evidence indicating that dopamine regulates various contextual fear processes, along with the more recent studies that have begun to elucidate the brain areas and neurophysiological mechanisms involved. From a fundamental research perspective, understanding how dopamine regulates contextual fear will lead to novel insights on the neurochemical modulation of neural circuit function underlying memory processing. This research may also have translational relevance given that contextual fear conditioning and extinction also provide useful preclinical models of certain aspects of anxiety-related disorders and their treatment

A comparison of psychological characteristics of standout police officers and Oregon Police Academy trainees

Police officers are frequently viewed as being unable to perform the duties assigned to them by society. Criticism has focused on inappropriate reaction to social unrest and an inability to control crime. Improving the selection process of police officers has been proposed as an appropriate means of improving police officer performance. The problem is how to improve the selection process to select individuals who will perform at the highest level. This study attempted to determine if personality traits of standout police officers, as measured by psychological tests, differ significantly from personality traits of recruit police officers. Considerable research in Oregon has been done on personality traits of police officers. The research has dealt with testing police officer applicants and recruit police officers. This study compared the psychological profile of police academy trainees with the psychological profile of standout police officers. The standout police officers were identified in a study by John Koroloff. The standard t test was used for a comparison of personality traits based on test scores from the Law Enforcement Assessment and Development Report (LEADR), the Psychopathic Deviate scale (PD) and the MacAndrew Alcoholism scale (MA) of the Minnesota Multiphasic Personality Inventory (MMPI), and the Wonderlic Personnel Test. The LEADR consists of the 16 Personality Factors (16PF), the Clinical Analysis Questionnaire (CAQ), and second-order factors. A comparison was also made of the age difference between the two groups. The hypothesis that there is no statistically significant difference between the two groups was only partially supported. Statistically significant differences were found on the Intelligence, Low Energy Depression, Paranoia, Psychasthenia, Depression, and Psychoticism scales of the LEADR; on the Psychopathic Deviate and MacAndrew Alcoholism scales of the MMPI; and on the age difference

Medial prefrontal cortex circuit function during retrieval and extinction of associative learning under anesthesia

Associative learning is encoded under anesthesia and involves the medial prefrontal cortex (mPFC). Neuronal activity in mPFC increases in response to a conditioned stimulus (CS+) previously paired with an unconditioned stimulus (US) but not during presentation of an unpaired stimulus (CS-) in anesthetized animals. Studies in conscious animals have shown dissociable roles for different mPFC subregions in mediating various memory processes, with the prelimbic (PL) and infralimbic (IL) cortex involved in the retrieval and extinction of conditioned responding, respectively. Therefore PL and IL may also play different roles in mediating the retrieval and extinction of discrimination learning under anesthesia. Here we used in vivo electrophysiology to examine unit and local field potential (LFP) activity in PL and IL before and after auditory discrimination learning and during later retrieval and extinction testing in anesthetized rats. Animals received repeated presentations of two distinct sounds, one of which was paired with footshock (US). In separate control experiments animals received footshocks without sounds. After discrimination learning the paired (CS+) and unpaired (CS-) sounds were repeatedly presented alone. We found increased unit firing and LFP power in PL and, to a lesser extent, IL after discrimination learning but not after footshocks alone. After discrimination learning, unit firing and LFP power increased in PL and IL in response to presentation of the first CS+, compared to the first CS-. However, PL and IL activity increased during the last CS- presentation, such that activity during presentation of the last CS+ and CS- did not differ. These results confirm previous findings and extend them by showing that increased PL and IL activity result from encoding of the CS+/US association rather than US presentation. They also suggest that extinction may occur under anesthesia and might be represented at the neural level in PL and IL

Sex differences in learned fear expression and extinction involve altered gamma oscillations in medial prefrontal cortex

Sex differences in learned fear expression and extinction involve the medial prefrontal cortex (mPFC). We recently demonstrated that enhanced learned fear expression during auditory fear extinction and its recall is linked to persistent theta activation in the prelimbic (PL) but not infralimbic (IL) cortex of female rats. Emerging evidence indicates that gamma oscillations in mPFC are also implicated in the expression and extinction of learned fear. Therefore we re-examined our in vivo electrophysiology data and found that females showed persistent PL gamma activation during extinction and a failure of IL gamma activation during extinction recall. Altered prefrontal gamma oscillations thus accompany sex differences in learned fear expression and its extinction. These findings are relevant for understanding the neural basis of post-traumatic stress disorder, which is more prevalent in women and involves impaired extinction and mPFC dysfunction

Improved functional connectivity network estimation for brain networks using multivariate partial coherence

OBJECTIVE: Graphical networks and network metrics are widely used to understand and characterise brain networks and brain function. These methods can be applied to a range of electrophysiological data including electroencephalography, local field potential and single unit recordings. Functional networks are often constructed using pair-wise correlation between variables. The objective of this study is to demonstrate that functional networks can be more accurately estimated using partial correlation than with pair-wise correlation. APPROACH: We compared network metrics derived from unconditional and conditional graphical networks, obtained using coherence and multivariate partial coherence (MVPC), respectively. Graphical networks were constructed using coherence and MVPC estimates, and binary and weighted network metrics derived from these: node degree, path length, clustering coefficients and small-world index. MAIN RESULTS: Network metrics were applied to simulated and experimental single unit spike train data. Simulated data used a 10x10 grid of simulated cortical neurons with centre-surround connectivity. Conditional network metrics gave a more accurate representation of the known connectivity: Numbers of excitatory connections had range 3-11, unconditional binary node degree had range 6-80, conditional node degree had range 2-13. Experimental data used multi-electrode array recording with 19 single-units from left and right hippocampal brain areas in a rat model for epilepsy. Conditional network analysis showed similar trends to simulated data, with lower binary node degree and longer binary path lengths compared to unconditional networks. SIGNIFICANCE: We conclude that conditional networks, where common dependencies are removed through partial coherence analysis, give a more accurate representation of the interactions in a graphical network model. These results have important implications for graphical network analyses of brain networks and suggest that functional networks should be derived using partial correlation, based on MVPC estimates, as opposed to the common approach of pair-wise correlation

Cannabinoid regulation of fear and anxiety: an update

Purpose of ReviewAnxiety- and trauma-related disorders are prevalent and debilitating mental illnesses associated with a significant socioeconomic burden. Current treatment approaches often have inadequate therapeutic responses, leading to symptom relapse. Here we review recent preclinical and clinical findings on the potential of cannabinoids as novel therapeutics for regulating fear and anxiety.Recent FindingsEvidence from preclinical studies has shown that the non-psychotropic phytocannabinoid cannabidiol and the endocannabinoid anandamide have acute anxiolytic effects and also regulate learned fear by dampening its expression, enhancing its extinction and disrupting its reconsolidation. The findings from the relevant clinical literature are still very preliminary but are nonetheless encouraging.SummaryBased on this preclinical evidence, larger-scale placebo-controlled clinical studies are warranted to investigate the effects of cannabidiol in particular as an adjunct to psychological therapy or medication to determine its potential utility for treating anxiety-related disorders in the future

In vitro activity of Camellia sinensis (green tea) against trophozoites and cysts of Acanthamoeba castellanii

© 2020 The Author(s) The effect of Camellia sinensis (green tea) on the growth of Acanthamoeba castellanii trophozoites was examined using a microplate based-Sulforhodamine B (SRB) assay. C. sinensis hot and cold brews at 75% and 100% concentrations significantly inhibited the growth of trophozoites. We also examined the structural alterations in C. sinensis-treated trophozoites using transmission electron microscopy (TEM) and scanning electron microscopy (SEM). This analysis showed that C. sinensis compromised the cell membrane integrity and caused progressive destruction of trophozoites. C. sinensis also significantly inhibited the parasite's ability to form cysts in a dose-dependent manner and reduced the rate of excystation from cysts to trophozoites. C. sinensis exhibited low cytotoxic effects on primary corneal stromal cells. However, cytotoxicity was more pronounced in SV40-immortalized corneal epithelial cells. Chromatographic analysis showed that both hot and cold C. sinensis brews contained the same number and type of chemical compounds. This work demonstrated that C. sinensis has anti-acanthamoebic activity against trophozoite and cystic forms of A. castellanii. Further studies are warranted to identify the exact substances in C. sinensis that have the most potent anti-acanthamoebic effect

Persistent prelimbic cortex activity contributes to enhanced learned fear expression in females

Anxiety disorders, such as post-traumatic stress, are more prevalent in women and are characterized by impaired inhibition of learned fear and medial prefrontal cortex (mPFC) dysfunction. Here we examined sex differences in fear extinction and mPFC activity in rats. Females showed more learned fear expression during extinction and its recall, but not fear conditioning. They also showed more spontaneous fear recovery and more contextual fear before extinction and its recall. Moreover, enhanced learned fear expression in females was associated with sustained prelimbic (PL) cortex activity. These results suggest that sex differences in learned fear expression may involve persistent PL activation

Sex differences in auditory fear discrimination are associated with altered medial prefrontal cortex function

The increased prevalence of post-traumatic stress disorder (PTSD) that is observed in women may involve sex differences in learned fear inhibition and medial prefrontal cortex (mPFC) function. PTSD is characterized by fear overgeneralization involving impaired fear regulation by safety signals. We recently found that males show fear discrimination and females show fear generalization involving reduced safety signalling after extended fear discrimination training. Here we determined if these sex differences involve altered mPFC function. Male and female rats underwent three days of auditory fear discrimination training, where one tone (CS+) was paired with footshock and another tone (CS-) was presented alone. Local field potentials were recorded from prelimbic (PL) and infralimbic (IL) mPFC during retrieval. We found that males discriminated and females generalized based on cue-induced freezing at retrieval. This was accompanied by sex differences in basal theta and gamma oscillations in PL and IL. Importantly, males also showed PL/IL theta activation during safety signalling by the CS- and IL gamma activation in response to the threat-related CS+, both of which were absent in females. These results add to growing evidence indicating that sex differences in learned fear inhibition are associated with altered mPFC function

Structural, functional, and metabolic alterations in human cerebrovascular endothelial cells during toxoplasma gondii infection and amelioration by verapamil in vitro

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Toxoplasma gondii (T. gondii), the causative agent of toxoplasmosis, is a frequent cause of brain infection. Despite its known ability to invade the brain, there is still a dire need to better understand the mechanisms by which this parasite interacts with and crosses the blood–brain barrier (BBB). The present study revealed structural and functional changes associated with infection and replication of T. gondii within human brain microvascular endothelial cells (BMECs) in vitro. T. gondii proliferated within the BMECs and disrupted the integrity of the cerebrovascular barrier through diminishing the cellular viability, disruption of the intercellular junctions and increasing permeability of the BMEC monolayer, as well as altering lipid homeostasis. Proton nuclear magnetic resonance (1H NMR)-based metabolomics combined with multivariate data analysis revealed profiles that can be attributed to infection and variations in the amounts of certain metabolites (e.g., amino acids, fatty acids) in the extracts of infected compared to control cells. Notably, treatment with the Ca2+ channel blocker verapamil rescued BMEC barrier integrity and restricted intracellular replication of the tachyzoites regardless of the time of treatment application (i.e., prior to infection, early-and late-infection). This study provides new insights into the structural and functional changes that accompany T. gondii infection of the BMECs, and sheds light upon the ability of verapamil to inhibit the parasite proliferation and to ameliorate the adverse effects caused by T. gondii infection