Training-induced changes in the expression of GABAA-associated genes in the amygdala after the acquisition and extinction of Pavlovian fear

Previous work suggests the gamma-aminobutyric acid (GABA)ergic system may be dynamically regulated during emotional learning. In the current study we examined training-induced changes in the expression of GABA(A)-related genes and the binding of GABA receptor radioligands in the amygdala after the acquisition and extinction of Pavlovian fear. Using in situ hybridization, we examined the expression pattern changes of mRNAs for GABAergic markers in the lateral, basolateral and central subdivisions of the amygdala in C57Bl/6J mice. These markers included GABA-synthesizing enzymes (GAD67 and GAD65), major GABA(A) receptor subunits (alpha1, alpha2, alpha3, alpha5, beta2 and gamma2) and the expression of mRNAs that are involved in a variety of GABA-related intracellular processes, including GABA transporter-1 (GAT1), GABA(A) receptor-associated protein and the GABA(A) clustering protein, gephyrin. With fear conditioning, we found decreased mRNA levels of alpha1, alpha5 and GAD67, as well as deceased benzodiazepine binding in the amygdala. Fear extinction induced an increase in mRNA levels of alpha2, beta2, GAD67 and gephyrin, as well as a decrease in GAT1. Together, these findings indicate that the acquisition of fear induced a downregulation of mRNA markers related to a decrease in amygdala GABAergic function, whereas the acquisition of fear extinction produced an upregulation of GABAergic markers related to enhanced GABAergic transmission.     

Neuropathological epidemiology of cerebral aging: a study of two genetic polymorphisms

We studied whether ApoE and -219 GT (ApoE promoter) polymorphism modulates neurofibrillary tangle (NFT) and senile plaque (SP) development in aging among 190 non-institutionalized individuals (mean age 79.5 years). Analysis revealed that the mean Braak stage was higher in epsilon4 allele carriers. Once individuals with Braak stage V were excluded (n = 5), relationships between NFT and the two genotypes studied were weak, whereas in epsilon4 allele carriers, the risk of SP was multiplied by 4 to 7 in four areas (CA1, subiculum, isocortex and entorhinal cortex). This association was more pronounced in subjects under 80 years and was also observed when analysis was restricted to Braak stages 0, I and II. Epsilon 2 allele carriers appeared to have fewer lesions but, due to limited numbers, this trend was not significant. In two regions (CA1, subiculum), the number of SP increased significantly for individuals who were homozygous for the T allele of -219 GT. However the association was no longer significant when controlling for ApoE epsilon4. It should be noted that the brain of elderly subjects carrying one epsilon4 allele may not undergo senile changes.     

Effects of Electronic Nicotine Delivery Systems and Cigarettes on Systemic Circulation and Blood-Brain Barrier: Implications for Cognitive Decline

Electronic nicotine delivery systems (often known as e-cigarettes) are a novel tobacco product with growing popularity, particularly among younger demographics. The implications for public health are twofold, as these products may represent a novel source of tobacco-associated disease but may also provide a harm reduction strategy for current tobacco users. There is increasing recognition that e-cigarettes impact vascular function across multiple organ systems. Herein, we provide a comparison of evidence regarding the role of e-cigarettes versus combustible tobacco in vascular disease and implications for blood-brain barrier dysfunction and cognitive decline. Multiple non-nicotinic components of tobacco smoke have been identified in e-cigarette aerosol, and their involvement in vascular disease is discussed. In addition, nicotine and nicotinic signaling may modulate peripheral immune and endothelial cell populations in a highly context-dependent manner. Direct preclinical evidence for electronic nicotine delivery system–associated neurovascular impairment is provided, and a model is proposed in which non-nicotinic elements exert a proinflammatory effect that is functionally antagonized by the presence of nicotine.

Widespread availability of electronic nicotine delivery systems (ENDS; alias e-cigarettes) has ushered in a new era of youth tobacco use and continues to raise urgent questions in the realm of public health and policy. In 2014, ENDS overtook cigarettes as the most commonly used tobacco product by high school students in the United States.¹ In the same year, use of any tobacco product by US high school students increased for the first time since 1998. Before this, rates had consistently trended downward, extending back to the adoption of youth tobacco reduction initiatives in the late 1990s. This inflection point is entirely attributable to ENDS, as all other tobacco product use has continued to decline. Furthermore, high school ENDS use in 2018 increased 77.8% over the previous year, representing the largest increase in youth tobacco use ever recorded by the CDC. ENDS are used by 27.5% of US high school students, with similar increases in prevalence emerging internationally.2, 3, 4 Although there is an inverse association between the age of individuals and their likelihood of ever using an ENDS, the prevalence of use in adults has also trended upward. Use estimates are much more divergent, but fell between 15% and 20% in 2015 to 2016.⁵Little is known regarding the safety and the long-term health impact of these products. Despite a trend toward vaporized polysubstance use, the vast majority of products contain nicotine.⁶ There are concerns that ENDSs may therefore be more addictive or increase the odds of future combustible cigarette use in adolescents. This concern has grown particularly urgent because of increasing concentrations of nicotine in recent products.⁷ The average concentration of nicotine has trended upward over time and is most notable in the case of Juul, in which the net nicotine content far exceeds that of cigarettes. Careful control over the fraction of protonated nicotine makes the delivery of more nicotine possible while minimizing the associated aversive effects. Changing the protonated fraction also impacts pharmacokinetics and sensory perceptions, potentially influencing addiction liability.⁸ In the arena of smoking cessation, ENDS may potentially represent a new tool for nicotine replacement that provides tactile and sensory cues similar to cigarettes. Whether they ultimately prove useful in this context will depend on their health profile balanced against their effectiveness in smoking reduction or cessation. The impact of ENDS on pulmonary function has garnered considerable attention, and both preclinical and clinical studies have begun to demonstrate airway inflammation and alterations in pulmonary immunity.⁹ Few studies directly address potential systemic (nonpulmonary) consequences, which are a significant contributor to tobacco-associated morbidity¹⁰ and may have a more insidious onset in ENDS users. ENDS have a relatively short history of use and, therefore, preclinical research is necessary to provide insight regarding these long-term health care and public health questions.     

Sight saving strategies for developing nations: toward an appropriate philosophy of blindness treatment and prevention for ministries of health, international agencies and mission societies in developing nations

Saving the sight of millions of blind people in Developing Nations requires the development of an appropriate philosophy of blindness treatment and prevention. Guidelines are presented in this paper, emphasizing the importance of training national workers, using appropriate ophthalmic technology and promoting international cooperation of governments, development agencies, and mission societies.     

Brazilian patients with panic disorder: the use of defense mechanisms and their association with severity

This study aims to evaluate the defense mechanisms most frequently used by Brazilian patients with panic disorder when compared with a control group. The study also examines the association between severity of disease and comorbidity and the use of specific defense mechanisms. Sixty panic-disordered patients and 31 controls participated in the study. The Mini International Neuropsychiatric Interview was used to confirm the panic disorder diagnosis and to establish the comorbid diagnosis. The Clinical Global Impression (CGI) was used to assess severity and the Defensive Style Questionnaire (DSQ-40) was used to evaluate the defense mechanisms. Panic patients used more neurotic (mean = 4.9 versus 3.6; p < 0.001) and immature (mean = 3.9 versus 2.8; p < 0.001) defenses as compared with controls. Panic patients with severe disease (n = 37; CGI>4) had more depression comorbidity and used more immature defenses than patients with CGI相似文献   

Infusion of apomorphine into the dorsocentral striatum produces acute drug-induced recovery from neglect produced by unilateral medial agranular cortex lesions in rats

Previous studies have shown that systemic administration of apomorphine is effective in producing acute drug-induced recovery from neglect induced by unilateral medial agranular cortex (AGm) lesions. More recent studies have demonstrated that recovery from neglect may be due to plastic changes occurring in the dorsal central striatum (DCS). Further, lesions of the DCS produce neglect that does not respond to systemic administration of apomorphine, suggesting that this area may be crucial for the therapeutic effects of apomorphine. In the present study, the behavioral effects of apomorphine infused into the DCS of animals with AGm lesion-induced neglect were examined to determine whether the DCS is a site of drug action. An infusion of 0.375 micro g of apomorphine into the DCS, but not a lateral striatal control area, was effective in producing acute recovery from neglect. The results of this study support the crucial role of the DCS in recovery from neglect induced by unilateral AGm lesions and suggest that the DCS may be an important site of action for the therapeutic effects of apomorphine. Because dopamine agonist therapy has been shown to be effective in humans with neglect, the results of the current study may represent an important step in the development of future pharmacotherapies.     

Destruction of the inferior colliculus disrupts the production and inhibition of fear conditioned to an acoustic stimulus

The inferior colliculus (IC) is the major source of auditory information involved in processing the behavioral significance of acoustic stimuli. In the current study, we assessed whether the IC is a critical source of information which mediates the expression of fear and the inhibition of fear conditioned to an auditory stimulus. Fear and the inhibition of fear were tested by measuring fear-potentiated startle. In Experiment 1, we demonstrated that rats which received electrolytic lesions of the IC failed to show fear-potentiated startle in the presence of a noise previously conditioned to elicit fear. In Experiment 2, we demonstrated that rats with similarly placed lesions of the IC failed to inhibit fear-potentiated startle in the presence of a noise previously conditioned to inhibit fear to a light. Thus, in both Experiments 1 and 2, lesions of the IC disrupted the behavioral significance of the noise stimulus. Together with previous findings, these results are consistent with the view that the IC is a common source of diverging auditory information used to mediate the fear eliciting and safety signal properties conditioned to auditory stimuli.     

CT findings in malignant meningiomas

Summary Recurrent meningiomas are due usually to incomplete removal as in the case of basal meningiomas where the tumour surrounding vessels and nervous structures cannot be completely excised. Recurrent meningiomas of the convexity are rare after resection. In most recurrent cases histological changes are noted which may explain the rapid growth, the aggressive nature and also the malignancy of the tumour. These changes include increased mitotic activity, necrosis and invasion of the adjacent brain parenchyma. CT findings in malignant meningiomas are related to the microscopic appearance of these tumours: tumoral necrosis determines heterogeneous enhancement; brain invasion explains the irregular outline of the tumour and sometimes the absence of surrounding low attenuation area. The authors report 5 malignant meningiomas in which the CT findings are correlated with the microscopic findings.Presented in part at the 17th Annual Meeting of the German Society of Neuroradiology, Tübingen, 8–10 October 1981.     

Effects of K+ and arginine on insulin, glucagon, and somatostatin release from the in vitro perfused rat pancreas

Rat pancreases were perfused in vitro for 5-min periods with K+ alone (8, 10, and 12 mM) or in the presence of arginine (10 mM). Alone, K+ caused bursts of insulin, glucagon, and somatostatin (SRIF) release; with arginine, it caused a burst of insulin and sustained SRIF release, but caused sustained suppression of glucagon. This suppression correlated better with SRIF than insulin release. Therefore, if a paracrine effect is responsible for the inhibition of glucagon secretion under these circumstances, SRIF is a more likely candidate than insulin.