Dual role of α7 nicotinic acetylcholine receptors in the retrosplenial cortex for aversive memory acquisition and retrieval.

In the retrosplenial cortex (RSC), the role of cholinergic modulation via α7 nicotinic receptors and their involvement in memory is unknown. In recent years, the RSC has been shown to deteriorate in the early stages of Alzheimer's disease (AD). Likewise, the cholinergic system has been postulated as one of those responsible for cognitive impairment in patients with AD. Great interest has arisen in the study of α7 nicotinic receptors as more specific targets for the treatment of this disease. For this reason, we aim to study the role of α7 receptors of the RSC in memory processing. We infused a selective α7 receptor antagonist into the anterior part of the RSC (aRSC) to assess its role in different phases of aversive memory processing using an inhibitory avoidance task. We found that α7 nicotinic receptors are involved in memory acquisition and expression, but not in its consolidation. These results identify aRSC α7 nicotinic receptors as key players in aversive memory processing and highlight their significant potential as therapeutic targets for Alzheimer's disease.

α7 nicotinic acetylcholine receptors in the medial prefrontal cortex control rewarding but not aversive memory expression in a dopamine-sensitive manner.

Emotional learning involves the association between sensory cues and rewarding or aversive stimuli, and this stored information can be recalled during memory retrieval. In this process, the medial prefrontal cortex (mPFC) plays an essential role. We have previously shown that the antagonism of α7 nicotinic acetylcholine receptors (nAChRs) by methyllycaconitine (MLA) in the mPFC blocked cue-induced cocaine memory retrieval. However, little is known about the involvement of prefrontal α7 nAChRs in the retrieval of aversive memories. Here, by using pharmacology and different behavioral tasks, we found that MLA did not affect aversive memory retrieval, indicating a differential effect of cholinergic prefrontal control of appetitive and aversive memories. Despite being shown that acetylcholine modulates dopamine release in the mPFC, it remains unknown if those modulatory systems act together to control reward-based behavior. We examined that question and found that dopamine type 1 receptor (D1R) activation prevented MLA-induced blockade of cocaine CPP retrieval. Our results suggest that α7 nAChRs and D1R signaling interact in the mPFC to modulate cocaine-associated memory retrieval.

α7 nicotinic acetylcholine receptor in memory processing.

Information storage in the brain involves different memory types and stages that are processed by several brain regions. Cholinergic pathways through acetylcholine receptors actively participate on memory modulation, and their disfunction is associated with cognitive decline in several neurological disorders. During the last decade, the role of α7 subtype of nicotinic acetylcholine receptors in different memory stages has been studied. However, the information about their role in memory processing is still scarce. In this review, we attempt to identify brain areas where α7 nicotinic receptors have an essential role in different memory types and stages. In addition, we discuss recent work implicating-or not-α7 nicotinic receptors as promising pharmacological targets for memory impairment associated with neurological disorders.

Early-Life Stress Reprograms Stress-Coping Abilities in Male and Female Juvenile Rats.

Prenatal stress (PS) is a major risk factor for the development of emotional disorders in adulthood that may be mediated by an altered hypothalamic-pituitary-adrenal axis response to stress. Although the early onset of stress-related disorders is recognized as a major public health problem, to date, there are relatively few studies that have examined the incidence of early-life stressors in younger individuals. In this study, we assessed PS impact on the stress-coping response of juvenile offspring in behavioral tests and in the induced molecular changes in the hippocampus. Furthermore, we assessed if pregnancy stress could be driving changes in patterns of maternal behavior during early lactation. We found that PS modified stress-coping abilities of both sex offspring. In the hippocampus, PS increased the expression of bdnf-IV and crfr1 and induced sex difference changes on glucocorticoids and BDNF mRNA receptor levels. PS changed the hippocampal epigenetic landscape mainly in male offspring. Stress during pregnancy enhanced pup-directed behavior of stressed dams. Our study indicates that exposure to PS, in addition to enhanced maternal behavior, induces dynamic neurobehavioral variations at juvenile ages of the offspring that should be considered adaptive or maladaptive, depending on the characteristics of the confronting environment. Our present results highlight the importance to further explore risk factors that appear early in life that will be important to allow timely prevention strategies to later vulnerability to stress-related disorders.

Prefrontal cortex nicotinic receptor inhibition by methyllycaconitine impaired cocaine-associated memory acquisition and retrieval.

Cocaine administration has been shown to induce plastic changes in the medial prefrontal cortex (mPFC), which could represent a mechanism by which cocaine facilitates the association between cocaine rewarding effects with contextual cues. Nicotinic acetylcholine receptors (nAChRs) in the mPFC have critical roles in cognitive function including attention and memory and are key players in plasticity processes. However, whether nAChRs in the mPFC are required for the acquisition and maintenance of cocaine-associated memories is still unknown. To assess this question, we used the conditioning place preference (CPP) model to study the effect of intra-mPFC infusion of methyllycaconitine, a selective antagonist of α7 nAChRs, on the acquisition, consolidation and expression of cocaine-associated memory in adult rats. Our findings reveal that mPFC α7 nAChRs activation is necessary for the acquisition and retrieval, but not consolidation, of cocaine induced CPP. Moreover, cocaine-induced sensitization during CPP conditioning sessions was abolished by methyllycaconitine infusion in the mPFC. Together, these results identify mPFC α7 nAChRs as critical players involved in both acquiring and retrieving cocaine-associated memories. Considering that drug seeking often depends on the association between drug-paired cues and the rewarding effects of the drug, α7 nAChRs in the mPFC could be considered as potential targets for the prevention or treatment of cocaine use disorder.

Medial prefrontal cortical control of reward- and aversion-based behavioral output: Bottom-up modulation.

How does the brain guide our actions? This is a complex issue, where the medial prefrontal cortex (mPFC) plays a crucial role. The mPFC is essential for cognitive flexibility and decision making. These functions are related to reward- and aversion-based learning, which ultimately drive behavior. Though, cortical projections and modulatory systems that may regulate those processes in the mPFC are less understood. How does the mPFC regulate approach-avoidance behavior in the case of conflicting aversive and appetitive stimuli? This is likely dependent on the bottom-up neuromodulation of the mPFC projection neurons. In this review, we integrate behavioral-, pharmacological-, and viral-based circuit manipulation data showing the involvement of mPFC dopaminergic, noradrenergic, cholinergic, and serotoninergic inputs in reward and aversion processing. Given that an incorrect balance of reward and aversion value could be a key problem in mental diseases such as substance use disorders, we discuss outstanding questions for future research on the role of mPFC modulation in reward and aversion.

Non-invasive biomarkers of fetal brain development reflecting prenatal stress: An integrative multi-scale multi-species perspective on data collection and analysis.

Prenatal stress (PS) impacts early postnatal behavioural and cognitive development. This process of 'fetal programming' is mediated by the effects of the prenatal experience on the developing hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS). We derive a multi-scale multi-species approach to devising preclinical and clinical studies to identify early non-invasively available pre- and postnatal biomarkers of PS. The multiple scales include brain epigenome, metabolome, microbiome and the ANS activity gauged via an array of advanced non-invasively obtainable properties of fetal heart rate fluctuations. The proposed framework has the potential to reveal mechanistic links between maternal stress during pregnancy and changes across these physiological scales. Such biomarkers may hence be useful as early and non-invasive predictors of neurodevelopmental trajectories influenced by the PS as well as follow-up indicators of success of therapeutic interventions to correct such altered neurodevelopmental trajectories. PS studies must be conducted on multiple scales derived from concerted observations in multiple animal models and human cohorts performed in an interactive and iterative manner and deploying machine learning for data synthesis, identification and validation of the best non-invasive detection and follow-up biomarkers, a prerequisite for designing effective therapeutic interventions.

Oscillating delayed feedback control schemes for stabilizing equilibrium points.

Limitations of the delayed feedback control and of its extended versions have been fully treated in the literature. The oscillating delayed feedback control appears as a promising scheme to overcome this problem. Two methods based on it are dealt with in this work. It is rigorously proven that for a nonlinear scalar system, stabilization in one of its (unstable) equilibrium points is achieved if any of these methods is applied. An ad-hoc map is associated to the (continuous) controlled system and the results are derived using discrete-time system stabilization tools. Moreover, the stability parameters region is fully described and issues like control performance, rate of convergence or robustness aspects are carefully analyzed.

The hydroethanolic Litchi chinensis leaf extract alleviate hepatic injury induced by carbon tetrachloride (CCl4) through inhibition of hepatic inflammation.

Various medicinal plants are traditionally used in a hepatoprotective manner, like, for example, the Litchi chinensis leaf infusion that is employed in Chinese medicine as liver tonics to strengthen hepatic functioning. In this context, the present study was designed to evaluate the hepatoprotective and acute toxicological effects of hydroethanolic L. chinensis leaf extract in HepG2 cells and mice. Specifically, the cytotoxicity and hepatoprotective activities of L. chinensis leaf extract were evaluated in HepG2 cells and in vivo against carbon tetrachloride (CCl4)-induced acute liver injury. The administration of CCl4 in mice provokes cell swelling, loss of sinusoid capillary spaces and structural disarrangement of the hepatic lobe, apoptosis and leukocyte infiltration. Further, CCl4 evokes an increase in serum alanine aminotransferase (ALT), tumor necrosis factor (TNF) and interleukin-6 (IL-6) levels in hepatic tissue. However, Silymarin, the positive control, and the L. chinensis extract were able to restore the viability of cells treated with CCl4 at all concentrations evaluated, reduced the inflammatory parameters, TNF and IL-6, reestablished hepatic tissue morphology and did not induce acute toxicological alterations. The data obtained underscore that the extract from L. chinensis leaves features hepatoprotective activity, corroborating with ethnopharmacological use, and does not lead to acute toxicological effects.

Prenatal stress increases adult vulnerability to cocaine reward without affecting pubertal anxiety or novelty response.

Prenatal stress (PS) induces long-lasting molecular alterations in brain circuits of the offspring and increases the propensity to develop neuropsychiatric diseases during adulthood, including mood disorders and drug addiction. A major goal of this study was to assess the impact of PS on pubertal behaviour and adult vulnerability to cocaine-induced conditioning place preference (CPP). We therefore evaluated pubertal novelty response and anxiety-like behaviour in control (C) and PS rats, and then, we examined cocaine-induced CPP in those animals during adulthood. We found no differences between C and PS groups on pubertal behaviour, however, only PS rats showed a significant cocaine-induced CPP. To further analyze our results, we classified cocaine-treated rats regarding their CPP score in Low CPP or High CPP and we then analysed their pubertal behaviour. We found different relations of anxiety-like behaviour to cocaine reward as a function of PS exposure: for C group, High CPP and Low CPP had shown similar levels of anxiety-like behaviour at puberty; on the contrary, for PS group, High CPP had shown lower anxiety-like behaviour than Low CPP rats. This study underscores the importance of considering prenatal exposure to stress when analysing the relationship between anxiety and cocaine vulnerability. Moreover, the evaluation of behavioural traits at puberty opens the possibility of early intervention and will allow the development of specific prevention strategies to avoid the devastating consequences of drug addiction later in life.

The malleable brain: plasticity of neural circuits and behavior - a review from students to students.

One of the most intriguing features of the brain is its ability to be malleable, allowing it to adapt continually to changes in the environment. Specific neuronal activity patterns drive long-lasting increases or decreases in the strength of synaptic connections, referred to as long-term potentiation and long-term depression, respectively. Such phenomena have been described in a variety of model organisms, which are used to study molecular, structural, and functional aspects of synaptic plasticity. This review originated from the first International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Alpbach, Austria (Sep 2016), and will use its curriculum and discussions as a framework to review some of the current knowledge in the field of synaptic plasticity. First, we describe the role of plasticity during development and the persistent changes of neural circuitry occurring when sensory input is altered during critical developmental stages. We then outline the signaling cascades resulting in the synthesis of new plasticity-related proteins, which ultimately enable sustained changes in synaptic strength. Going beyond the traditional understanding of synaptic plasticity conceptualized by long-term potentiation and long-term depression, we discuss system-wide modifications and recently unveiled homeostatic mechanisms, such as synaptic scaling. Finally, we describe the neural circuits and synaptic plasticity mechanisms driving associative memory and motor learning. Evidence summarized in this review provides a current view of synaptic plasticity in its various forms, offers new insights into the underlying mechanisms and behavioral relevance, and provides directions for future research in the field of synaptic plasticity. Read the Editorial Highlight for this article on page 788. Cover Image for this issue: doi: 10.1111/jnc.13815.

Ipomoea pes-caprae (L.) R. Br (Convolvulaceae) relieved nociception and inflammation in mice - A topical herbal medicine against effects due to cnidarian venom-skin contact.

ETHNOPHARMACOLOGICAL RELEVANCE: Ipomoea pes-caprae is known as bayhops, beach morning glory or goat's foot, and in Brazil as salsa-de-praia. Its leaves are used in worldwide folk medicine for the relief of jellyfish-stings symptoms. The literature only reports the neutralizing effects of nonpolar plant derived over jellyfish venoms, without validating the popular use or exploring the mechanism of action. AIM OF THE STUDY: This study aimed to evaluate and validate the topical effects of a semisolid containing hydroethanolic extract obtained from the aerial parts of I. pes-caprae using different models of paw- and ear-oedema and spontaneous nociception in mice, attempting to better understand the mechanism involved in its effect. MATERIALS AND METHODS: Leaf and stem of I. pes-caprae were extracted by ethanol 50% (v/v) and the soft-extract was incorporated in Hostacerin® cream base at 0.5%, 1.0% and 2% (w/w). The anti-hypersensitivity effects were evaluated by injecting the Physalia physalis venom into the right mice's hindpaw pre-treated either with the semisolid containing the I. pes-caprae extract or with the isolated majority compound 3,5-Di-O-caffeoylquinic acid (ISA). The topical anti-inflammatory activity was investigated using both preclinical models: paw oedema induced by trypsin, bradykinin (BK), histamine and carrageenan, and ear oedema induced by capsaicin. Additionally, the model of spontaneous nociception induced by trypsin and capsaicin were used to verify the topical antinociceptive activity. RESULTS: The animals pre-treated with the semisolid containing I. pes-caprae extract or with the intraplantar injection of the major component (ISA) had the mechanical hypersensitivity induced by P. physalis venom significantly reduced. Significant inhibition was also observed in paw-oedema induced by trypsin, histamine and BK, and in a less extent in carrageenan-induced paw oedema. Similar effect was observed in mice challenged to the capsaicin-induced ear-oedema. Besides the vascular effects, the extract interfered with leukocyte migration induced by histamine injection. Finally, the semisolid presented significant inhibition in trypsin- and capsaicin-induced spontaneous nociception. CONCLUSIONS: The hydroethanolic extract of I. pes-caprae showed compliance with the topical popular use of the herbal product to relieve the symptoms evoked by the cnidarian venom-skin contact, such as neurogenic oedema and nociception. The extract components seem to interfere with the effects resulting from the TRPV1, B2R and PAR-2 activation, once it interfered with painful-behaviour and oedema induced by capsaicin, BK and trypsin, pointing the histaminergic system as the main target, once it is an important mediator in the signalling pathway of the aforementioned receptors.

Unravelling the Link Between Prenatal Stress, Dopamine and Substance Use Disorder.

Substance use disorder (SUD) refers to the detrimental use of psychoactive substances and it is related to a cluster of behavioural, cognitive and physiological dysfunctions indicating that the individual continues using the substance despite significant substance-related problems. Although it is one of the most prevalent neuropsychiatric diseases affecting society worldwide, the mechanism underlying the vulnerability of certain individuals is not well understood yet. It is now widely accepted that, in addition to genetic factors, environmental adversities during critical stages of development of an organism could also be considered as risk factors that contribute to SUD. It has been suggested that prenatal stress (PS) could play an important role in the causal mechanisms of SUD, since it was shown that PS leads individuals to poor stress management and behavioural problems, both of which increase the risk of SUD. It is widely accepted that gestational stress exposure in rats interferes with the correct progeny development. In particular, research in this field points out that the development of the mesocorticolimbic dopaminergic (DA) system is sensitive to disruption by exposure to early stressors. Interestingly, PS induces behavioural abnormalities that are similar to those observed in individuals that present SUD. Since dysfunction of mesocorticolimbic DA pathway has been reported in both prenatally stressed and SUD individuals, in this review we will summarise the current knowledge supporting that PS may serve as a strong candidate to explain the vulnerability of certain individuals to develop SUD following repeated drug exposure. We will also propose a mechanistic hypothesis to explain PS-induced changes on mesocorticolimbic DA system.

The effect of previous exposure to nicotine on nicotine place preference.

RATIONALE: Prior exposure to drugs of abuse may increase or decrease the reinforcing effects of the drug in later consumptions. Based on the initial locomotor activity (LA) response to an acute drug administration or to novelty in an open-field arena, animals can be classified as low or high LA responders (LR or HR). Few studies have used this classification with nicotine, and the results are controversial. Some authors suggested that nicotine can induce conditioned-place preference (CPP) following prior nicotine exposure, whereas others suggested that previous nicotine exposure extinguishes nicotine-CPP. OBJECTIVE: To explore if the administration of nicotine in a novel environment without explicit behavioral consequences to classify animals in low and high nicotine responders (LNR and HNR) could affect the establishment of nicotine CPP in male Sprague-Dawley rats. RESULTS: Prior exposure to a single dose of nicotine (0.4 mg/kg, subcutaneously) induced CPP in LNR rats after 14 days of conditioning (seven-trial) but not after two or eight conditioning days. In contrast, HNR rats did not show CPP under any condition. In addition, our results indicated that previous exposure to nicotine decreased its rewarding effects in eight conditioning days CPP (four-trial), which can be regularly established without prior exposure to nicotine. CONCLUSION: The results suggested that response to a single exposure to nicotine predicts the acquisition of nicotine preference in a 14-day conditioning protocol only for LNR rats. Thus, our findings demonstrated the relevance of using LNR and HNR classification when the individual susceptibility to nicotine preference is studied.

Histone deacetylase inhibition decreases preference without affecting aversion for nicotine.

Epigenetic mechanisms have recently been shown to be involved in the long-term effects of drugs of abuse. A well described epigenetic mechanism modulating transcriptional activity consists in the binding to DNA of methyl-CpG binding proteins, such as MeCP2, recruiting histone deacetylases (HDACs). Nicotine causes long-term changes in the brain, but little is known concerning the mechanisms involved in nicotine-preference. Using a nicotine-conditioned place preference protocol, we demonstrate here that the histone deacetylase inhibitor phenylbutyrate was able to dramatically reduce the preference for nicotine, without altering the aversive properties of the drug. We measured immunohistochemically the acetylation of lysine-9 of histone H3, and the expression of phosphorylated cAMP-response element-binding protein, HDAC2 and methyl-CpG-binding protein 2 in the striatum and prefrontal cortex of rats displaying nicotine-preference or aversion and treated with phenylbutyrate. We show that, at the dose administered, the inhibitor was effective in inhibiting HDAC activity. The data suggest that phosphorylated cAMP-response element-binding protein participates in the establishment of conditioned place preference, but not in the reduction of nicotine-preference in response to phenylbutyrate. Moreover, striatal expression of HDAC2 in response to phenylbutyrate mirrored the behavioral effects of the inhibitor, suggesting that HDAC2 is involved in promoting synaptic plasticity underlying the preference for nicotine.

Nicotine-conditioned place preference induced CREB phosphorylation and Fos expression in the adult rat brain.

RATIONALE: Experimental evidence indicates that nicotine causes long-lasting changes in the brain associated with behavior. Although much has been learned about factors participating in this process, less is known concerning the mechanisms and brain areas involved in nicotine preference. OBJECTIVES: The objective of this study is to examine the participation of brain structures during the development of nicotine-conditioned place preference (CPP). METHODS: To identify brain regions activated in CPP, we have measured the levels of phosphorylated cyclic AMP response element binding protein (pCREB) and Fos protein using a behavioral CPP and conditioned place aversion (CPA) paradigms. RESULTS: Rats developed reliable and robust CPP and also CPA. During nicotine preference and reinstatement behaviors, a significant increase of both pCREB and Fos protein expression occurs in the nucleus accumbens (NAc) and ventral tegmental area (VTA) and also in the prefrontal cortex (PFC), dorsal striatum (DStr), amygdala, and hippocampus. These increases were abolished by the administration of mecamylamine or by a CPA protocol, showing a specific activation of pCREB in drug preference animals, mediated by nicotinic receptors. Specifically in the VTA, nicotine-induced preference and reinstatement of the preference caused the activation of dopaminergic and GABAergic cells in different proportions. CONCLUSION: The results indicate that the phosphorylation of CREB and expression of Fos protein, as indicators of neural activity, accompany the acquisition and maintenance of nicotine-induced CPP but not CPA in mesolimbic areas (NAc, VTA, PFC, and DStr) as well as in memory consolidation structures (hippocampus and amygdala) and nicotinic receptor are involved in this process. Taken together, these studies identify the brain regions where pCREB activity is essential for nicotine preference.

Quiste del ligamento redondo, una lesión rara que simula una hernia inguinal: reporte de un caso / Round ligament cyst, a rare condition simulating inguinal hernia: case report

Cysts of the inguinal cord are disorders that simulate inguinal hernias and manifest as inguinal masses and, in some cases, are accompanied by pain that can simulate a complicated inguinal hernia. We report the third case of a round ligament cyst in a 21-year-old female with a mass in the right inguinal area with intermittent pain. The patient was subjected to surgical exploration of the right inguinal area where a round ligament cyst was found. The ligament was resected and reported as a serous cyst. The patient's outcome was excellent and she was discharged 24 h after surgery. She has been followed up for 3 months without recurrence. Round ligament cysts are very rare disorders, and the diagnosis is perioperative. Resection of the round ligament causes complete symptom relief, and every case requires inguinal hernioraphy.

[Round ligament cyst, a rare condition simulating inguinal hernia. Case report]. / Quiste del ligamento redondo, una lesión rara que simula una hernia inguinal. Reporte de un caso.

Cysts of the inguinal cord are disorders that simulate inguinal hernias and manifest as inguinal masses and, in some cases, are accompanied by pain that can simulate a complicated inguinal hernia. We report the third case of a round ligament cyst in a 21-year-old female with a mass in the right inguinal area with intermittent pain. The patient was subjected to surgical exploration of the right inguinal area where a round ligament cyst was found. The ligament was resected and reported as a serous cyst. The patient's outcome was excellent and she was discharged 24 h after surgery. She has been followed up for 3 months without recurrence. Round ligament cysts are very rare disorders, and the diagnosis is perioperative. Resection of the round ligament causes complete symptom relief, and every case requires inguinal hernioraphy.