Alterations of learning and memory are accompanied by alterations in the expression of 5-HT receptors, glucocorticoid receptor and brain-derived neurotrophic factor in different brain regions of an animal model of depression generated by neonatally male treatment with clomipramine in male rats.

Depressive illness has been associated with impaired cognitive processes accompanied by reduced neurotrophin levels, especially brain-derived neurotrophic factor (BDNF), and dysfunctions in the hypothalamic-pituitary-adrenal (HPA) axis. In addition, depression is characterized by a decreased functioning of the serotonergic system due to changes in the activity or expression of its receptors including, most significantly, 5-HT1A, 5-HT2A, and 5-HT3 in brain regions that regulate mood, emotions, and memory, such as the prefrontal cortex, hippocampus, and amygdala. In this regard, rats treated with clomipramine (CMI) in the neonatal stage show depression-like behaviors that persist into adulthood; hence, this constitutes an adequate model of depression for exploring various molecular aspects associated with the etiology of this disorder. This, study, then, was designed to analyze the long-term effects of early postnatal exposure to CMI on the expression of 5-HT1A, 5-HT2A, and 5-HT3 receptors, as well as BDNF and GR in the following brain regions: PFC, amygdala, hippocampus, and hypothalamus, which could be related to alterations in memory and learning, as evaluated using the novel object recognition (NOR) and Morris water maze (MWM). Expression of the 5-HT1A, 5-HT2A, and 5-HT3 receptors, BDNF, and the glucocorticoid receptor (GR) was assessed by RT-qPCR in the four aforementioned brain regions, all of which play important roles in the control of memory and mood. Findings show that neonatal treatment with CMI causes alterations in memory and learning, as indicated by alterations in the results of the MWM and NOR tests. Expression of the 5-HT1A receptor increased in the hippocampus, amygdala, and hypothalamus, but decreased in the PFC, while the 5-HT2A and BDNF receptors decreased their expression in the PFC, amygdala, and hippocampus. There was no change in the expression of the 5-HT3 receptor. In addition, expression of GR in the hippocampus and PFC was low, but increased in the hypothalamus. Taken together, these data show that neonatal CMI treatment produces permanent molecular changes in brain regions related to learning and memory that could contribute to explaining the behavioral alterations observed in this model.

Depression and Pain: Use of Antidepressants.

BACKGROUND: Emotional disorders are common comorbid affectations that exacerbate the severity and persistence of chronic pain. Specifically, depressive symptoms can lead to an excessive duration and intensity of pain. Clinical and preclinical studies have been focused on the underlying mechanisms of chronic pain and depression comorbidity and the use of antidepressants to reduce pain. AIM: This review provides an overview of the comorbid relationship of chronic pain and depression, the clinical and pre-clinical studies performed on the neurobiological aspects of pain and depression, and the use of antidepressants as analgesics. METHODS: A systematic search of literature databases was conducted according to pre-defined criteria. The authors independently conducted a focused analysis of the full-text articles. RESULTS: Studies suggest that pain and depression are highly intertwined and may co-exacerbate physical and psychological symptoms. One important biochemical basis for pain and depression focuses on the serotonergic and norepinephrine system, which have been shown to play an important role in this comorbidity. Brain structures that codify pain are also involved in mood. It is evident that using serotonergic and norepinephrine antidepressants are strategies commonly employed to mitigate pain Conclusion: Literature indicates that pain and depression impact each other and play a prominent role in the development and maintenance of other chronic symptoms. Antidepressants continue to be a major therapeutic tool for managing chronic pain. Tricyclic antidepressants (TCAs) are more effective in reducing pain than Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin- Noradrenaline Reuptake Inhibitors (SNRIs).

Corrigendum: Cognitive Impairment After Resolution of Hepatic Encephalopathy: A Systematic Review and Meta-Analysis.

[This corrects the article DOI: 10.3389/fnins.2021.579263.].

Cognitive Impairment After Resolution of Hepatic Encephalopathy: A Systematic Review and Meta-Analysis.

Hepatic encephalopathy (HE) is one of the most disabling metabolic diseases. It consists of a complication of liver disease through the action of neurotoxins, such as excessive production of ammonia from liver, resulting in impaired brain function. Its prevalence and incidence are not well known, although it has been established that up to 40% of cirrhotic patients may develop HE. Patients with HE episodes display a wide range of neurological disturbances, from subclinical alterations to coma. Recent evidence suggests that the resolution of hepatic encephalopathy does not fully restore cognitive functioning in cirrhotic patients. Therefore, the aim of this review was to evaluate the evidence supporting the presence of lingering cognitive deficits in patients with a history of HE compared to patients without HE history and how liver transplant affects such outcome in these patients. We performed two distinct meta-analysis of continuous outcomes. In both cases the results were pooled using random-effects models. Our results indicate that cirrhotic patients with a history of HE show clear cognitive deficits compared control cirrhotic patients (Std. Mean Difference (in SDs) = -0.72 [CI 95%: -0.94, -0.50]) and that these differences are not fully restored after liver transplant (Std. Mean Difference (in SDs) = -0.72 [CI 95%: -0.94, -0.50]).

Neonatal treatment with clomipramine modifies the expression of estrogen receptors in brain areas of male adult rats.

The participation of estrogens in depression has been well recognized. To exert its effects, estradiol binds mainly to estrogen receptors ESR1 and ESR2 (α and ß, respectively), expressed in brain regions including the hippocampus, limbic regions and hypothalamic nuclei. In rodents, modified estrogen receptors expression in brain areas have been implicated in different signs similar to those observed in depressive patients. Neonatal clomipramine (CMI) treatment is a pharmacological manipulation that generates behavioral and neurochemical changes that persist throughout adulthood and resemble human depression. The aim of this study was to analyze whether CMI neonatal treatment modifies the expression of nuclear ESR1 and ESR2 in the hippocampus, amygdala basolateral (BLA), amygdala medial (MeA), hypothalamic medial preoptic area (mPOA) and raphe nucleus in male rats. Our results indicate that CMI treatment significantly induced an mRNA increase of ESR1 in the hypothalamus, additionally produce a reduction in the mRNA ESR2 expression in raphe accompanied of an increase in hypothalamus and amygdala. CMI treated rats show more immunorreactive cells to ESR1 (ESR1-ir) in mPOA, BLA, MeA, together with a reduction of these cells in the hippocampal CA1 region. Moreover, an increase in the number of immunorreactive cells to ESR2 (ESR2-ir), in BLA and MeA, was observed in CMI treated rats. Additionally, the hippocampal CA2 region and raphe nucleus showed a decrease in these cells. Also, neonatal CMI treatment induced a decrease in the number of cells of the pyramidal layer in CA1. Overall, the results suggest that neonatal CMI treatment in rats (during brain development) induces changes in estrogen receptors in different brain areas involved with the regulation of depressive-like behaviors.

Seaweeds-derived compounds modulating effects on signal transduction pathways: A systematic review.

BACKGROUND: Recently, the study of marine natural products has gained interest due to their relevant biological activities. Specially, seaweeds produce bioactive compounds that could act as modulators of cell signaling pathways involved in a plethora of diseases. Thereby, the description of the molecular mechanisms by which seaweeds elicit its biological functions will certainly pave the way to the pharmacological development of drugs. AIM: This review describes the molecular mechanisms by which seaweeds act and its possible utilization in the design of new drugs. METHODS: This review was conducted according to the PRISMA-P guidelines for systematic reviews. Two independent authors searched into four different databases using combinations of keywords. Two more authors selected the articles following the eligibility criteria. Information extraction was conducted by two separated authors and entered into spreadsheets. Methodological quality and risk of bias were determined applying a 12-question Risk of Bias criteria tool. RESULTS AND DISCUSSION: We found 2360 articles (SCOPUS: 998; PubMed: 678; Wiley: 645 and EBSCO: 39) using the established keywords, of which 113 articles fit the inclusion criteria and were included in the review. This work comprises studies in cell lines, and animal models, any clinical trial was excluded. The articles were published from 2005 up to March 31st 2018. The biggest amount of articles was published in 2017. Furthermore, the seaweeds tested in the studies were collected in 15 countries, mainly in Eastern countries. We found that the main modulated signaling pathways by seaweeds-derivate extracts and compounds were: L-Arginine/NO, TNF-α, MAPKs, PI3K/AKT/GSK, mTOR, NF-κB, extrinsic and intrinsic apoptosis, cell cycle, MMPs and Nrf2. Finally, the articles we analyzed showed moderate risk of bias in almost all the parameters evaluated. However, the studies fail to describe the place and characteristics of sample collection, the sample size, and the blindness of the experimental design. CONCLUSION: In this review we identified and summarized relevant information related to seaweed-isolated compounds and extracts having biological activity; their role in different signal pathways to better understand their potential to further development of cures for cancer, diabetes, and inflammation-related diseases.

The neonatal treatment with clomipramine decreases sexual motivation and increases estrogen receptors expression in the septum of male rats: Effects of the apomorphine.

Administering clomipramine during the early days of life induced several behavioral and neurochemical alterations in adult male rats, which resemble major depression disorder. The alterations included poor sexual performance, which is considered a reward-seeking behavior regulated by dopaminergic system. Given that estrogen receptors are expressed in different areas of the brain involved in regulating reproductive behavior, motivation and mood. The objective of this study was to analyze the effect of a non-selective dopamine agonist (apomorphine) on sexual incentive motivation in rats exposed to clomipramine (CMI) in the neonatal period. In addition, we evaluated the expression of mRNA ERα and ERß in nucleus accumbens (NAcc) and septum of CMI rats. We found that only a few rats subjected to neonatal CMI treatment performed mounts, intromissions and ejaculations. Also, those rats spent less time exploring the sexual incentive zone and had lower preference scores; this effect was reverted by administering 0.1 mg/kg of apomorphine. Finally, the CMI rats presented higher levels of mRNA ERα and ERß, only in septum area. These data indicate that neonatal treatment with CMI altered the expression of mRNA ERα and ERß in the septum, which participates in regulating the motivational component of sexual behavior.

Early postnatal treatment with clomipramine induces female sexual behavior and estrous cycle impairment.

Administration of clomipramine (CMI), a tricyclic antidepressant, in early stages of development in rats, is considered an animal model for the study of depression. This pharmacological manipulation has induced behavioral and physiological alterations, i.e., less pleasure-seeking behaviors, despair, hyperactivity, cognitive dysfunction, alterations in neurotransmitter systems and in HPA axis. These abnormalities in adult male rats are similar to the symptoms observed in major depressive disorders. One of the main pleasure-seeking behaviors affected in male rats treated with CMI is sexual behavior. However, to date, no effects of early postnatal CMI treatment have been reported on female reproductive cyclicity and sexual behavior. Therefore, we explored CMI administration in early life (8-21 PN) on the estrous cycle and sexual behavior of adult female rats. Compared to the rats in the early postnatal saline treatment (CTRL group), the CMI rats had fewer estrous cycles, fewer days in the estrous stage, and longer cycles during a 20-day period of vaginal cytology analysis. On the behavioral test, the CMI rats displayed fewer proceptive behaviors (hopping, darting) and had lower lordosis quotients. Also, they usually failed to display lordosis and only rarely manifested marginal or normal lordosis. In contrast, the CTRL rats tended to display normal lordosis. These results suggest that early postnatal CMI treatment caused long-term disruptions of the estrous cycle and female sexual behavior, perhaps by alteration in the hypothalamic-pituitary-gonadal (HPG) axes and in neuronal circuits involved in the regulation of the performance and motivational of sexual behavior as the noradrenergic and serotonergic systems.

Chronic treatment with estradiol restores depressive-like behaviors in female Wistar rats treated neonatally with clomipramine.

Neonatal administration of clomipramine (CMI) induces diverse behavioral and neurochemical alterations in adult male rats that resemble major depression disorder. However, the possible behavioral alterations in adult female rats subjected to neonatal treatment with clomipramine are unknown. Therefore, the aim of this study was to explore the effect of neonatal treatment with CMI on adult female rats in relation to locomotion and behavioral despair during the estrus cycle. Also evaluated was the effect of chronic treatment with E2 on these female CMI rats. We found no effects on spontaneous locomotor activity due to neonatal treatment with CMI, or after 21days of E2 administration. In the FST, neonatal treatment with CMI increased immobility and decreased active swimming and climbing behaviors. Influence of the ovarian cycle was detected only in relation to climbing behavior, as the rats in the MD phase displayed less climbing activity. Chronic E2 administration decreased immobility but increased only swimming in CMI rats. These results suggest that neonatal treatment with CMI induces despair-like behavior in female rats, but that chronic E2 administration generates antidepressant-like behavior by decreasing immobility and increasing swimming, perhaps through interaction with the serotonergic system.

An alarm pheromone increases the responsivity of amygdaline-hippocampal neurons / Una feromona de alarma incrementa la responsividad de neuronas amigdalino-hipocampales

The capability to perceive and emit alarm substances, such as 2-heptanone, makes animals aware of the presence of danger, leading to some strategies directed towards survival. Strategies of survival involve emotional memory which is processed by deep temporal lobe structures, such as amygdaloid complex and hippocampus. In the Wistar rat, 2-heptanone produces anxiety-like behavior and an increased firing rate of basal amygdaline neurons. However, it is unknown whether 2-heptanone modifies the responsivity of medial amygdaline-hippocampal connection. Therefore, we placed a group (n=10) of Wistar rats in a plexiglass cage impregnated with 2-heptanone. Rats from control group (n=10) were introduced into a similar clean cage. Twenty four hours later we obtained single-unit extracellular recordings from the hippocampus (CA1-CA3) neurons identified by their connection to medial amygdala. Although the basal neuronal firing rate was similar between groups, first order interval distribution histogram analysis showed that 2-heptanone produced shorter intervals of firing rate. Peristimulus histograms indicated that: i) the amygdaline stimulation produces an increased firing rate in hippocampal neurons; and ii) this response is increased and enlarged on the 2-heptanone group. Since a single exposure to an alarm pheromone seems to facilitate the amygdala-hippocampal connection, results suggest the initial formation of contextual memories related with fear.

La percepción olfatoria de feromonas de alarma, como la 2-heptanona, promueve ciertas estrategias de supervivencia con la participación de la memoria emocional, integrada en estructuras del lóbulo temporal, como la amígdala y el hipocampo. En la rata Wistar, la olfacción de 2-heptanona genera conductas sugerentes de ansiedad y un incremento de la tasa de disparo neuronal del núcleo basal de la amígdala. Sin embargo, no se conoce si la 2-heptanona modifica la responsividad de la conexión amígdala medial-hipocampo. Un grupo de ratas Wistar (n=10) fue colocado dentro de una caja de acrílico impregnada con 2-heptanona; el grupo control (n=10) fue introducido en una caja limpia. Veinticuatro horas después se obtuvo el registro unitario extracelular de neuronas del hipocampo (CA1-CA3) identificadas por su conexión con la amígdala medial. Aunque la tasa de disparo basal fue similar entre los grupos experimentales, el histograma de distribución de intervalos de primer orden indicó un predominio de intervalos de breve duración en el grupo 2-heptanona. Los histogramas periestímulo indicaron que: i) las neuronas hipocampales responden con un incremento en la tasa de disparo neuronal ante la estimulación amigdalina; ii) la respuesta es de mayor magnitud y duración en el grupo previamente expuesto a 2-heptanona. Dado que una sola exposición a una feromona de alarma facilita la conexión amígdala medial-hipocampo, los resultados sugieren la formación inicial de una memoria contextual relacionada con el miedo.

Anterior olfactory organ removal produces anxiety-like behavior and increases spontaneous neuronal firing rate in basal amygdala.

Some chemical cues may produce signs of anxiety and fear mediated by amygdala nuclei, but unknown is the role of two anterior olfactory epithelial organs, the septal and vomeronasal organs (SO-VNOs). The effects of SO-VNO removal were explored in different groups of Wistar rats using two complementary approaches: (i) the assessment of neuronal firing rate in basal and medial amygdala nuclei and (ii) behavioral testing. Fourteen days after SO-VNO removal, spontaneous activity in basal and medial amygdala nuclei in one group was determined using single-unit extracellular recordings. A separate group of rats was tested in the elevated plus maze, social interaction test, and open field test. Compared with sham-operated and intact control rats, SO-VNO removal produced a higher neuronal firing rate in the basal amygdala but not medial amygdala. In the behavioral tests, SO-VNO removal increased signs of anxiety in the elevated plus maze, did not alter locomotion, and increased self-directed behavior, reflecting anxiety-like behavior. Histological analysis showed neuronal destruction in the accessory olfactory bulb but not anterior olfactory nucleus in the SO-VNO group. The present results suggest the participation of SO-VNO/accessory olfactory bulb/basal amygdala relationships in the regulation of anxiety through a process of disinhibition.

2-Heptanone increases the firing rate of the basal amygdala: role of anterior olfactory epithelial organs.

Wistar rats subjected to physical stress release a urine alarm pheromone (2-heptanone) that produces signs of anxiety and despair in receptor rats not subjected to physical stress. However, unknown are the effects of 2-heptanone on the firing rate of the basal amygdala, a structure that participates in the expression of fear, and the participation of anterior olfactory epithelial organs, namely the septal organ and vomeronasal organ (SO-VNO). We explored the effects of 2-heptanone applied near the nostrils on single-unit extracellular recordings from the basal amygdala in a sham-operated group and rats that underwent removal of the SO-VNO. The firing rate of basal amygdala neurons in the SO-VNO removal group was significantly higher than in the sham-operated group. In both groups, recordings were classified according to the responses to 2-heptanone (i.e., increased firing rate, decreased firing rate, and no response). SO-VNO removal was associated with an increased firing rate in the three types of neurons. A similar number of neurons increased their firing rate during and after 2-heptanone stimulation in both groups, but such an increase in firing rate was longer in the group of rats subjected to SO-VNO removal. The results indicate that the SO-VNO is not essential for the effect of 2-heptanone on the firing rate of basal amygdala neurons. SO-VNO ablation did not block but rather accentuated the response of amygdala neurons to 2-heptanone.

Testosterone reduces cumulative burying in female Wistar rats with minimal participation of estradiol.

Testosterone exerts anxiolytic effects, but the participation of its aromatase metabolic product estradiol is controversial. Therefore, we used the defensive burying paradigm in female Wistar rats to explore testosterone's (1.0 mg/rat, s.c.) interactions with picrotoxin (a noncompetitive gamma-aminobutyric acid-A receptor [GABA(A)] antagonist; 1.0 mg/kg, i.p.), formestane (an aromatase inhibitor; 3.0 mg/rat, s.c.), and tamoxifen (an estrogen receptor-beta antagonist; 1.0 mg/kg, s.c.). Serum levels of testosterone, estradiol, and progesterone were determined in the same rats. Burying latency and locomotion did not significantly change. Systemic testosterone administration enhanced serum testosterone and estradiol levels and reduced defensive burying. This reduction in total burying was blocked by pretreatment with picrotoxin and tamoxifen, but not formestane. We conclude that testosterone produced anxiolytic-like effects in female rats that were mediated by actions at the GABA(A) receptor, with participation of the estradiol receptor-beta, rather than estradiol aromatization.

Estrés psicosocial: algunos aspectos clínicos y experimentales / Psychosocial stress: some clinical and experimental aspects

El presente trabajo aborda conceptos actuales del estrés, resaltando el de tipo social. El estrés psicosocial es un factor que predispone al desarrollo de diversas enfermedades en el ser humano cuyos efectos impactan sobre su calidad de vida y de salud. Se han identificado y diferenciado algunos de los factores sociales que producen estrés. Sin embargo, dadas las dificultades metodológicas y éticas para estudiar los efectos del estrés psicosocial en el ser humano, ha sido necesario diseñar modelos animales en los que se emplean estresores psicosociales a los que se enfrentan los animales cuando viven en grupo, por ejemplo el modelo de derrota social. Los datos provenientes de estos modelos han permitido entender algunos de los mecanismos neurobiológicos que subyacen al desarrollo de psicopatologías derivadas del estrés social, identificándose algunas de las estructuras participantes, como la amígdala del lóbulo temporal y a partir de estudios clínicos en seres humanos se ha identificado el papel que desempeña la corteza prefrontal en la toma de decisiones y en la planeación de respuestas conductuales socialmente apropiadas

The present revision approaches the definition of the concept of stress generated by different social factors. Psychosocial stress induces diverse pathologies in human being, contributing to health perturbation. The study of the effects of psychosocial stress in the human is limited since methodological and ethical considerations; however, the observation of the strategies to cope with stress in animal models, as well as its neurobiological correlates is a useful tool for the neurobiological study of psychosocial stress. For example, in the social defeat the display some signs suggesting an increased anxiety and despair, both processes involve the participation of the amygdala, and from some clinical studies in human it has additionally been suggested the involvement of the prefrontal cortex portion, in the decisionmaking process and the selection of the socially appropriated response