Acquisition of conditioned responding in a multiple schedule depends on the reinforcement's temporal contingency with each stimulus

Forty mice acquired conditioned responses to stimuli presented in a multiple schedule with variable inter-trial intervals (ITIs). In some trials, reinforcement was preceded by a variable conditioned stimulus (CS), while other trials were reinforced following distinctive fixed-duration CS. A third stimulus was presented but never paired with reinforcement. Subjects in five groups experienced ITIs of different durations. Acquisition of responding to each stimulus depended only on the cycle-to-trial ratio (C/T), and thus on the temporal contingency of each stimulus. Acquisition was unaffected by whether CSs were of fixed or variable duration

Emerging roles of brain metabolism in cognitive impairment and neuropsychiatric disorders

Here we discuss the role of diverse environmental manipulations affecting cognition with special regard to psychiatric conditions. We present evidence supporting a direct causal correlation between the valence of the environmental stimulation and some psychopathological traits and how the environment influences brain structure and function with special regard to oxidative stress and mitochondrial activity. Increasing experimental evidence supports a role for mitochondrial dysfunctions in neuropsychiatric disorders. Brain mitochondria are considered crucial mediators of allostasis, that is the capability to adapt to stress via a complex interaction between the autonomic, metabolic, and immune systems to maintain cellular homeostasis. In this process, mitochondria act as highly dynamic integrators by sensing and transducing stressors into adaptation mechanisms via metabolic stress mediators, such as glucocorticoids and catecholamines. Alterations in cellular homeostasis induced by chronic stress are thought to predispose to disease by triggering the so-called “mitochondrial allostatic load”. This process is characterized by functional and structural changes of the mitochondria, ultimately leading to oxidative stress, inflammation, mitochondrial DNA damage and apoptosis. In this review we discuss the role of diverse environmental manipulations to affect cognition with special regard to psychiatric conditions. How the environment influences brain structure and function, and the interactions between rearing conditions, oxidative stress and mitochondrial activity are fundamental questions that are still poorly understood. As will be discussed, increasing experimental evidence supports a role for mitochondrial dysfunctions in neuropsychiatric disorders. Brain mitochondria are considered crucial mediators of allostasis, that is the capability to adapt to stress via a complex interaction between the autonomic, metabolic, and immune systems to maintain cellular homeostasis. In this process, mitochondria act as highly dynamic integrators by sensing and transducing stressors into adaptation mechanisms via metabolic stress mediators, such as glucocorticoids and catecholamines. Alterations in cellular homeostasis induced by chronic stress are thought to predispose to disease by triggering the so-called “mitochondrial allostatic load”. This process is characterized by functional and structural changes of the mitochondria, ultimately leading to oxidative stress, inflammation, mitochondrial DNA damage and apoptosis. The brain requires considerable mitochondrial reserve not only to sustain basal neuronal needs but a also to provide increasing energy demands during stress. Consistently with these high energetic requirements, it is reasonable to hypothesise that the brain is particularly vulnerable to mitochondrial defects. Thus, even subtle metabolic alterations might have a substantial impact on cognitive functions. Over the last decade, several experimental evidence supported the hypothesis that a suboptimal mitochondrial function, which could be of genetic origin or acquired following adverse life events, is a key vulnerability factor for stress-related psychopathologies. Chronic psychological stress is a major promoter of anxiety as well as of oxidative damage, as shown in several studies. Recent evidence from mouse models harbouring mutations in mitochondrial genes demonstrated the role of mitochondria in modulating the response to acute psychological stress. However, it has yet to be determined whether mitochondrial dysfunctions are the cause or the consequence of anxiety. In this review, we discuss how adverse psychosocial environments can impact mitochondrial bioenergetics at the molecular level and we gather evidence from several studies linking energy metabolism and stress resilience/vulnerability. Moreover, we review recent findings supporting that metabolic dysfunction can underlie deficits in complex social behaviours. As will be discussed, aberrations in mitochondrial functionality have been found in the nucleus accumbens of highly anxious mice and mediate low social competitiveness. In addition, alterations in sociability can be reversed by enhancing mitochondrial functions. Recent evidence also demonstrated that a specific mutation in mitochondrial DNA, previously linked to autism spectrum disorder, produces autistic endophenotypes in mice by altering respiration chain and reactive oxygen species (ROS) production. Finally, we discuss a “Negative Enrichment” model that can explain some of the psychopathological conditions relevant to humans. Evidence of a direct causal correlation of valence of environmental stimulation and psychopathological traits will be presented, and possible molecular mechanisms that focus on oxidative stress. Collectively, the findings described here have been achieved with a wide set of behavioural and cognitive tasks with translational validity. Thus, they will be useful for future work aimed to elucidate the fine metabolic alterations in psychopathologies and devise novel approaches targeting mitochondria to alleviate these conditions

Altered fronto-striatal functions in the Gdi1 -null mouse model of X-linked Intellectual Disability

RAB-GDP dissociation inhibitor 1 (GDI1) loss-of-function mutations are responsible for a form of non-specific X-linked Intellectual Disability (XLID) where the only clinical feature is cognitive impairment. GDI1 patients are impaired in specific aspects of executive functions and conditioned response, which are controlled by fronto-striatal circuitries. Previous molecular and behavioral characterization of the Gdi1-null mouse revealed alterations in the total number/distribution of hippocampal and cortical synaptic vesicles as well as hippocampal short-term synaptic plasticity, and memory deficits. In this study, we employed cognitive protocols with high translational validity to human condition that target the functionality of cortico-striatal circuitry such as attention and stimulus selection ability with progressive degree of complexity. We previously showed that Gdi1-null mice are impaired in some hippocampus-dependent forms of associative learning assessed by aversive procedures. Here, using appetitive-conditioning procedures we further investigated associative learning deficits sustained by the fronto-striatal system. We report that Gdi1-null mice are impaired in attention and associative learning processes, which are a key part of the cognitive impairment observed in XLID patients

Mitogen and Stress-activated Protein Kinase 1 Negatively Regulates Hippocampal Neurogenesis

Neurogenesis in the subgranular zone (SGZ) of the adult hippocampus can be stimulated by a variety of means, including via exposure of experimental animals to an enriched environment that provides additional sensory, social, and motor stimulation. Tangible health and cognitive benefits accrue in enriched animals, including the amelioration of signs modelling psychiatric, neurological and neurodegenerative conditions that affect humans, which may in part be due to enhanced production of neurons. A key factor in the neuronal response to enrichment is the release of brain-derived neurotrophic factor (BDNF) and the activation of the Mitogen-Activated Protein Kinase (MAPK) cascade, which can lead to the stimulation of neurogenesis. Mitogen- and Stress-Activated protein Kinase 1 (MSK1) is a nuclear enzyme downstream of BDNF and MAPK that regulates transcription. MSK1 has previously been implicated in both basal and stimulated neurogenesis on the basis of studies with mice lacking MSK1 protein. In the present study, using mice in which only the kinase activity of MSK1 is lacking, we show that the rate of cellular proliferation in the SGZ (Ki-67 staining) is unaffected by the MSK1 kinase-dead (KD) mutation, and no different from controls levels after five weeks of enrichment. However, compared to wild-type mice, the number of doublecortin (DCX)-positive cells was greater in both standard-housed and enriched MSK1 KD mice. These observations suggest that, while MSK1 does not influence the basal rate of proliferation of neuronal precursors, MSK1 negatively regulates the number of cells destined to become neurons, potentially as a homeostatic control on the number of new neurons integrating into the dentate gyrus

A proteomic signature for CNS adaptations to the valence of environmental stimulation

Environmental Enrichment leads to a significant improvement in long-term performance across a range of cognitive functions in mammals and it has been shown to produce an increased synaptic density and neurogenesis. Nevertheless it is still an open question as to whether some key aspects of spatial learning & memory and procedural learning might be embodied by different molecular pathways to those of social cognition. Associated with synaptic changes and potentially underlying conditions, the Ras-ERK pathway has been proposed to be the primary mediator of in vivo adaptations to environmental enrichment, acting via the downstream Ras-ERK signalling kinase MSK1 and the transcription factor CREB. Herein, we show that valence of environmental stimulation increased social competition and that this is associated with a specific proteomic signature in the frontal lobe but notably not in the hippocampus. Specifically, we show that altering the valence of environmental stimuli affected the level of social competition, with mice from negatively enriched environments winning significantly more encounters—even though mice from positive were bigger and should display dominance. This behavioural phenotype was accompanied by changes in the proteome of the fronto-ventral pole of the brain, with a differential increase in the relative abundance of proteins involved in the mitochondrial metabolic processes of the TCA cycle and respiratory processes. Investigation of this proteomic signature may pave the way for the elucidation of novel pathways underpinning the behavioural changes caused by negative enrichment and further out understanding of conditions whose core feature is increased social competition

Risk factors associated with the low birth weight. Yara municipality. January – December, 2017

La reducción del bajo peso al nacer constituye una prioridad en el sistema nacional de salud en nuestro país por ser un determinante para disminuir la mortalidad infantil. El presente trabajo tiene como objetivo determinar los principales factores de riesgo asociados al bajo peso al nacer en el municipio Yara. Provincia Granma. Se realizó un estudio descriptivo de corte transversal, que incluyó a 26 gestantes que aportaron los nacimientos con bajo peso en el periodo de enero - diciembre 2017. Se analizaron las variables edad materna, evaluación nutricional al inicio del embarazo, edad gestacional al momento del parto, tipo de bajo peso, antecedentes patológicos materna y enfermedades asociadas con el embarazo.  Se produjeron 567 nacimientos, de los cuales, 26 mostraron un peso inferior a 2500 gramos y un índice de bajo peso al nacer de 4,8 %. Los factores de riesgo más significativos fueron el parto pretérmino, con 17 neonatos (65,38 %), 19 (73,07 %) gestantes presentaron infección vaginal, 13 (50 %) sufrieron anemia y 10 (38,4 %) madres desarrollaron la enfermedad hipertensiva gestacional dentro de las enfermedades asociadas a la gestación, la hipertensión arterial resulto ser el antecedente patológico materno más significativo con 3 gestantes (11,53 %), entre las 32-36 semanas de gestación ocurrieron 18 nacimientos (69,23 %) y 16 gestantes con valoración nutricional normopeso al inicio de la gestación aportaron el mayor número de bajo peso (61,53 %). Se concluyó que la identificación y modificación precoz de los factores de riesgo podría disminuir la incidencia del bajo peso al nacer.The reduction of low birth weight constitutes a priority in the national health system in our country because it is a determinant to reduce infant mortality. The objective of this study is to determine the main risk factors associated with low birth weight in the Yara municipality. Granma Province. A descriptive cross-sectional study was carried out, which included 26 pregnant women who provided births with low weight in the period of January - December 2017. The variables of maternal age, nutritional assessment at the beginning of pregnancy, gestational age at the time of delivery were analyzed, type of low weight, maternal pathological history and diseases associated with pregnancy. There were 567 births, of which 26 showed a weight below 2500 grams and a low birth weight index of 4.8 %. The most significant risk factors were preterm delivery, with 17 neonates (65.38 %), 19 (73.07 %) pregnant women presented vaginal infection, 13 (50 %) suffered from anemia and 10 (38.4 %) mothers developed gestational hypertensive disease in the diseases associated with pregnancy, arterial hypertension was the most significant maternal pathological history with 3 pregnant women (11.53 %), between 32-36 weeks of gestation occurred 18 births (69.23 % ) and 16 pregnant women with normal weight nutritional assessment at the beginning of pregnancy gave the highest number of low weight (61.53 %). It was concluded that the identification and early modification of risk factors could reduce the incidence of low birth weight.

The Kinase Function of MSK1 Regulates BDNF Signaling to CREB and Basal Synaptic Transmission, But Is Not Required for Hippocampal Long-Term Potentiation or Spatial Memory

The later stages of long-term potentiation (LTP) in vitro and spatial memory in vivo are believed to depend upon gene transcription. Accordingly, considerable attempts have been made to identify both the mechanisms by which transcription is regulated and indeed the gene products themselves. Previous studies have shown that deletion of one regulator of transcription, the mitogen- and stress-activated kinase 1 (MSK1), causes an impairment of spatial memory. Given the ability of MSK1 to regulate gene expression via the phosphorylation of cAMP response element binding protein (CREB) at serine 133 (S133), MSK1 is a plausible candidate as a prime regulator of transcription underpinning synaptic plasticity and learning and memory. Indeed, prior work has revealed the necessity for MSK1 in homeostatic and experience-dependent synaptic plasticity. However, using a knock-in kinase-dead mouse mutant of MSK1, the current study demonstrates that, while the kinase function of MSK1 is important in regulating the phosphorylation of CREB at S133 and basal synaptic transmission in hippocampal area CA1, it is not required for metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD), two forms of LTP or several forms of spatial learning in the watermaze. These data indicate that other functions of MSK1, such as a structural role for the whole enzyme, may explain previous observations of a role for MSK1 in learning and memory

Fatores de risco para infecção respiratória aguda em crianças menores de um ano. Veguitas. Yara Granma 2018

Acute respiratory infections have a high incidence in infants under one year. A descriptive, cross-sectional study was conducted to identify risk factors associated with acute respiratory infections in children under one year of age, in the Ramón Heredia Umpierre polyclinic, in the Yara municipality, Granma province, in the period January - August 2018. The universe It consisted of 86 infants under one year of age with acute respiratory infection. A form was prepared that included risk factors, which constituted the variables: age, sex, mixed and artificial lactation, low birth weight, overcrowding, incomplete immunization, smoking parents, possession of domestic animals and associated diseases. The most significant risk factors were mixed and artificial lactation (68.6%), possession of domestic animals (60.4%) and parental smoking (44.1%). Modification of risk factors for acute respiratory infections may decrease the incidence of the disease.Las infecciones respiratorias agudas tienen alta incidencia en los infantes menores de un año. Se realizó un estudio descriptivo, corte transversal, para identificar factores de riesgo asociados a las infecciones respiratorias agudas en menores de un año, en la policlínica Ramón Heredia Umpierre, del municipio Yara, provincia Granma, en el periodo Enero - agosto 2018. El universo estuvo constituido por 86 infantes menores de un año con infección respiratoria aguda. Se confeccionó una planilla que recogió factores de riesgo, que constituyeron las variables: edad, sexo, lactancia mixta y artificial, bajo peso al nacer, hacinamiento, inmunización incompleta, padres fumadores, posesión de animales domésticos y enfermedades asociadas. Los factores de riesgo más significativo fueron: lactancia mixta y artificial (68,6 %), posesión de animales domésticos (60,4%) y el hábito de fumar de los padres (44,1 %). La modificación de factores de riesgo de las infecciones respiratorias agudas puede disminuir la incidencia de la enfermedad.As infecções respiratórias agudas têm uma alta incidência em bebês com menos de um ano. Foi realizado um estudo transversal e descritivo para identificar fatores de risco associados a infecções respiratórias agudas em crianças menores de um ano, na policlínica Ramón Heredia Umpierre, no município de Yara, província de Granma, no período de janeiro a agosto de 2018. O universo Consistia em 86 crianças com menos de um ano de idade com infecção respiratória aguda. Foi elaborado um formulário que incluía fatores de risco, que constituíam as variáveis: idade, sexo, lactação mista e artificial, baixo peso ao nascer, superlotação, imunização incompleta, pais fumantes, posse de animais domésticos e doenças associadas. Os fatores de risco mais significativos foram lactação mista e artificial (68,6%), posse de animais domésticos (60,4%) e tabagismo dos pais (44,1%). A modificação dos fatores de risco para infecções respiratórias agudas pode diminuir a incidência da doença.