Exploring the Role of Neuroplasticity in Development, Aging, and Neurodegeneration.

Neuroplasticity refers to the ability of the brain to reorganize and modify its neural connections in response to environmental stimuli, experience, learning, injury, and disease processes. It encompasses a range of mechanisms, including changes in synaptic strength and connectivity, the formation of new synapses, alterations in the structure and function of neurons, and the generation of new neurons. Neuroplasticity plays a crucial role in developing and maintaining brain function, including learning and memory, as well as in recovery from brain injury and adaptation to environmental changes. In this review, we explore the vast potential of neuroplasticity in various aspects of brain function across the lifespan and in the context of disease. Changes in the aging brain and the significance of neuroplasticity in maintaining cognitive function later in life will also be reviewed. Finally, we will discuss common mechanisms associated with age-related neurodegenerative processes (including protein aggregation and accumulation, mitochondrial dysfunction, oxidative stress, and neuroinflammation) and how these processes can be mitigated, at least partially, by non-invasive and non-pharmacologic lifestyle interventions aimed at promoting and harnessing neuroplasticity.

Influence of alcohol and tobacco consumption on maternal and perinatal outcomes of puerperal women attended at the Brazilian National Health System / Influência do consumo de álcool e tabaco em desfechos maternos e perinatais de puérperas atendidas no Sistema Único de Saúde

Abstract Objectives: to evaluate the association between alcohol and tobacco consumption during pregnancy with maternal and child health conditions. Methods: cross-sectional study with a probabilistic sample of pregnant women living in Santa Catarina who conducted prenatal care and childbirth in the public national health service in 2019. A face-to-face survey questionnaire was applied to 3,580 pregnant women including maternal health issues during pregnancy and perinatal health of the newborn. Crude logistic regression analyzes were performed and adjusted for socio-demographic and maternal health conditions. Results: the prevalence of alcohol and tobacco consumption during pregnancy was 7.2% and 9.3%, respectively. Alcohol consumption during pregnancy increased the chance of maternal anemia by 45% (CI95%=1.09-1.91), increased the chance of gestational diabetes by 73% (CI95%=1.14-2.63) and reduced the chance of hypertension (OR=0.59; CI95%=0.37-0.94). Tobacco consumption doubled the chance of low birth weight (OR=2.16; CI95%=1.33-3.51). Conclusion: the consumption of alcoholic beverages during pregnancy increased the chance of maternal health complications, such as anemia and gestational diabetes, while tobacco increased the chance of low birth weight.

Resumo Objetivos: avaliar a associação entre o consumo de álcool e de tabaco durante a gravidez com condições de saúde maternas e da criança. Métodos: estudo transversal com amostra probabilística de gestantes residentes em Santa Catarina que realizaram o pré-natal e o parto na rede pública do estado em 2019. Foi aplicado questionário face-a-face com 3.580 gestantes incluindo questões de saúde maternas durante a gestação e saúde perinatal do recém-nascido. Foram realizadas análises de regressão logística brutas e ajustadas para condições sócio-demográficas e de saúde maternas. Resultados: as prevalências de consumo de bebidas alcoólicas e de tabaco durante a gestação foram de 7,2% e 9,3%, respectivamente. O consumo de álcool durante a gestação aumentou em 45% a chance de anemia materna (IC95%=1,09-1,91) e em 73% a de diabetes gestacional (IC95%=1,14-2,63) e reduziu a chance de hipertensão (OR=0,59; IC95%=0,37-0,94). O consumo de tabaco dobrou a chance de baixo peso gestacional ao nascer (OR=2,16; IC95%=1,33-3,51). Conclusão: o consumo de bebidas alcoólicas durante a gestação aumentou a chance de intercorrências de saúde maternas, como anemia e diabetes gestacional, enquanto o tabaco aumentou a chance de baixo peso ao nascer.

[Sedentary behavior and association with multimorbidity and patterns of multimorbidity in elderly Brazilians: data from the Brazilian National Health Survey, 2019]. / Comportamento sedentário e associação com multimorbidade e padrões de multimorbidade em idosos brasileiros: dados da Pesquisa Nacional de Saúde de 2019.

Sedentary behavior emerges as an important determinant of health in elderly persons, but its relationship to multimorbidity and its patterns in the Brazilian population have received little attention in epidemiological studies. Such associations can assist the elaboration of public policies aimed at modification of this behavior. This study thus aimed to assess the association between sedentary behavior and multimorbidity and its patterns in elderly Brazilians. This was a cross-sectional study of 43,554 elderly Brazilians in the Brazilian National Health Survey, 2019. Self-reported SB was categorized as < 3; 3-6; and > 6 hours a day. The presence of multimorbidity and its patterns were analyzed by self-report of two or more chronic diseases, where the three established patterns considered the diseases with similar clinical characteristics: (1) cardiopulmonary; (2) vascular-metabolic; and (3) mental-musculoskeletal. The associations were measured by binary logistic regression. Elderly persons that spent 3-6 hours/day in sedentary behavior had lower odds (OR = 1.39; 95%CI: 1.29; 1.50) of presenting multimorbidity, vascular-metabolic pattern (OR = 1.39; 95%CI: 1.29; 1.50), and mental-musculoskeletal pattern (OR = 1.11; 95%CI: 1.00; 1.24). Sedentary behavior > 6 hours/day was associated with higher odds of multimorbidity (OR = 1.58; 95%CI: 1.43; 1.74) and the cardiopulmonary (OR = 1.73; 95%CI: 1.33; 2.27), vascular-metabolic (OR = 1.49; 95%CI: 1.35; 1.64), and mental-musculoskeletal (OR = 1.15; 95%CI: 1.01; 1.31) patterns when compared to elders with 3 hours/day of sedentary behavior. This showed that extensive time in sedentary behavior is a relevant risk factor for multimorbidity and its patterns in the elderly.

O comportamento sedentário emerge como um importante determinante da saúde da pessoa idosa, no entanto, sua relação com a multimorbidade e seus padrões de acometimento em estudos epidemiológicos têm sido pouco explorados na população brasileira. Tais associações poderão auxiliar na elaboração de políticas públicas visando à modificação desse comportamento. Assim, o objetivo deste estudo foi avaliar a associação entre comportamento sedentário com multimorbidade e seus padrões em idosos brasileiros. Estudo transversal, com 43.554 idosos da Pesquisa Nacional de Saúde de 2019. O comportamento sedentário autorreferido foi categorizado em < 3; 3-6; e > 6 horas por dia. A presença de multimorbidade e seus padrões foram analisados pelo autorrelato da coexistência de duas ou mais doenças crônicas, sendo que os três padrões estabelecidos consideraram as doenças com características clínicas similares: (1) cardiopulmonar; (2) vascular-metabólico; e (3) mental-musculoesquelético. As associações foram realizadas pela regressão logística binária. Os idosos que despendiam 3-6 horas/dia em comportamento sedentário tiveram maiores chances (OR = 1,39; IC95%: 1,29; 1,50) de apresentar multimorbidade, padrão vascular-metabólico (OR = 1,39; IC95%: 1,29; 1,50) e mental-musculoesquelético (OR = 1,11; IC95%: 1,00; 1,24). Quando o comportamento sedentário foi > 6 horas/dia, houve maiores chances de multimorbidade (OR = 1,58; IC95%: 1,43; 1,74) e dos padrões cardiopulmonar (OR = 1,73; IC95%: 1,33; 2,27), vascular-metabólico (OR = 1,49; IC95%: 1,35; 1,64) e mental-musculoesquelético (OR = 1,15; IC95%: 1,01; 1,31), quando comparados àqueles que ficavam até 3 horas/dia. Dessa forma, evidenciou-se que tempos elevados em comportamento sedentário são fatores de risco relevantes para a ocorrência de multimorbidade e seus padrões em idosos.

El comportamiento sedentario emerge como un importante determinante de salud en personas ancianas, no obstante, su relación con la multimorbilidad y los patrones de enfrentamiento a la misma en estudios epidemiológicos se han investigado poco en la población brasileña. Tales asociaciones podrán apoyar en la elaboración de políticas públicas, con vistas a la modificación de ese comportamiento. Por ello, el objetivo de este estudio fue evaluar la asociación entre comportamiento sedentario con multimorbilidad y sus patrones en ancianos brasileños. Es un estudio transversal, con 43.554 ancianos de la Encuesta Nacional de Salud de 2019. El comportamiento sedentario autoinformado se categorizó en < 3; 3-6; y > 6 horas por día. La presencia de multimorbilidad y sus patrones se analizaron mediante el autoinforme de la coexistencia de dos o más enfermedades crónicas, siendo que los tres patrones establecidos consideraron las enfermedades con características clínicas similares: (1) cardiopulmonar; (2) vascular-metabólica y (3) mental-musculoesquelética. Las asociaciones fueron realizadas mediante regresión logística binaria. Los ancianos que pasaban 3-6h/día en comportamiento sedentario tuvieron mayores oportunidades (OR = 1,39; IC95%: 1,29; 1,50) de presentar multimorbilidad, patrón vascular-metabólico (OR = 1,39; IC95%: 1,29; 1,50) y mental-musculoesquelético (OR = 1,11; IC95%: 1,00; 1,24). Cuando el comportamiento sedentario fue > 6 horas/día hubo mayores oportunidades de multimorbilidad (OR = 1,58; IC95%: 1,43; 1,74), y de los patrones cardiopulmonar (OR = 1,73; IC95%: 1,33; 2,27), vascular-metabólico (OR = 1,49; IC95%: 1,35; 1,64) y mental-musculoesquelético (OR = 1,15; IC95%: 1,01; 1,31), cuando se compara con aquellos que estaban hasta 3 horas/día. De esa forma, se evidenció que tiempos elevados en comportamiento sedentario se mostraron factores de riesgo relevantes para la ocurrencia de multimorbilidad y sus patrones en ancianos.

Comportamento sedentário e associação com multimorbidade e padrões de multimorbidade em idosos brasileiros: dados da Pesquisa Nacional de Saúde de 2019 / Sedentary behavior and association with multimorbidity and patterns of multimorbidity in elderly Brazilians: data from the Brazilian National Health Survey, 2019 / Comportamiento sedentario y su asociación con la multimorbilidad y patrones de multimorbilidad en ancianos brasileños: datos de la Encuesta Nacional de Salud de 2019

Resumo: O comportamento sedentário emerge como um importante determinante da saúde da pessoa idosa, no entanto, sua relação com a multimorbidade e seus padrões de acometimento em estudos epidemiológicos têm sido pouco explorados na população brasileira. Tais associações poderão auxiliar na elaboração de políticas públicas visando à modificação desse comportamento. Assim, o objetivo deste estudo foi avaliar a associação entre comportamento sedentário com multimorbidade e seus padrões em idosos brasileiros. Estudo transversal, com 43.554 idosos da Pesquisa Nacional de Saúde de 2019. O comportamento sedentário autorreferido foi categorizado em < 3; 3-6; e > 6 horas por dia. A presença de multimorbidade e seus padrões foram analisados pelo autorrelato da coexistência de duas ou mais doenças crônicas, sendo que os três padrões estabelecidos consideraram as doenças com características clínicas similares: (1) cardiopulmonar; (2) vascular-metabólico; e (3) mental-musculoesquelético. As associações foram realizadas pela regressão logística binária. Os idosos que despendiam 3-6 horas/dia em comportamento sedentário tiveram maiores chances (OR = 1,39; IC95%: 1,29; 1,50) de apresentar multimorbidade, padrão vascular-metabólico (OR = 1,39; IC95%: 1,29; 1,50) e mental-musculoesquelético (OR = 1,11; IC95%: 1,00; 1,24). Quando o comportamento sedentário foi > 6 horas/dia, houve maiores chances de multimorbidade (OR = 1,58; IC95%: 1,43; 1,74) e dos padrões cardiopulmonar (OR = 1,73; IC95%: 1,33; 2,27), vascular-metabólico (OR = 1,49; IC95%: 1,35; 1,64) e mental-musculoesquelético (OR = 1,15; IC95%: 1,01; 1,31), quando comparados àqueles que ficavam até 3 horas/dia. Dessa forma, evidenciou-se que tempos elevados em comportamento sedentário são fatores de risco relevantes para a ocorrência de multimorbidade e seus padrões em idosos.

Abstract: Sedentary behavior emerges as an important determinant of health in elderly persons, but its relationship to multimorbidity and its patterns in the Brazilian population have received little attention in epidemiological studies. Such associations can assist the elaboration of public policies aimed at modification of this behavior. This study thus aimed to assess the association between sedentary behavior and multimorbidity and its patterns in elderly Brazilians. This was a cross-sectional study of 43,554 elderly Brazilians in the Brazilian National Health Survey, 2019. Self-reported SB was categorized as < 3; 3-6; and > 6 hours a day. The presence of multimorbidity and its patterns were analyzed by self-report of two or more chronic diseases, where the three established patterns considered the diseases with similar clinical characteristics: (1) cardiopulmonary; (2) vascular-metabolic; and (3) mental-musculoskeletal. The associations were measured by binary logistic regression. Elderly persons that spent 3-6 hours/day in sedentary behavior had lower odds (OR = 1.39; 95%CI: 1.29; 1.50) of presenting multimorbidity, vascular-metabolic pattern (OR = 1.39; 95%CI: 1.29; 1.50), and mental-musculoskeletal pattern (OR = 1.11; 95%CI: 1.00; 1.24). Sedentary behavior > 6 hours/day was associated with higher odds of multimorbidity (OR = 1.58; 95%CI: 1.43; 1.74) and the cardiopulmonary (OR = 1.73; 95%CI: 1.33; 2.27), vascular-metabolic (OR = 1.49; 95%CI: 1.35; 1.64), and mental-musculoskeletal (OR = 1.15; 95%CI: 1.01; 1.31) patterns when compared to elders with 3 hours/day of sedentary behavior. This showed that extensive time in sedentary behavior is a relevant risk factor for multimorbidity and its patterns in the elderly.

Resumen: El comportamiento sedentario emerge como un importante determinante de salud en personas ancianas, no obstante, su relación con la multimorbilidad y los patrones de enfrentamiento a la misma en estudios epidemiológicos se han investigado poco en la población brasileña. Tales asociaciones podrán apoyar en la elaboración de políticas públicas, con vistas a la modificación de ese comportamiento. Por ello, el objetivo de este estudio fue evaluar la asociación entre comportamiento sedentario con multimorbilidad y sus patrones en ancianos brasileños. Es un estudio transversal, con 43.554 ancianos de la Encuesta Nacional de Salud de 2019. El comportamiento sedentario autoinformado se categorizó en < 3; 3-6; y > 6 horas por día. La presencia de multimorbilidad y sus patrones se analizaron mediante el autoinforme de la coexistencia de dos o más enfermedades crónicas, siendo que los tres patrones establecidos consideraron las enfermedades con características clínicas similares: (1) cardiopulmonar; (2) vascular-metabólica y (3) mental-musculoesquelética. Las asociaciones fueron realizadas mediante regresión logística binaria. Los ancianos que pasaban 3-6h/día en comportamiento sedentario tuvieron mayores oportunidades (OR = 1,39; IC95%: 1,29; 1,50) de presentar multimorbilidad, patrón vascular-metabólico (OR = 1,39; IC95%: 1,29; 1,50) y mental-musculoesquelético (OR = 1,11; IC95%: 1,00; 1,24). Cuando el comportamiento sedentario fue > 6 horas/día hubo mayores oportunidades de multimorbilidad (OR = 1,58; IC95%: 1,43; 1,74), y de los patrones cardiopulmonar (OR = 1,73; IC95%: 1,33; 2,27), vascular-metabólico (OR = 1,49; IC95%: 1,35; 1,64) y mental-musculoesquelético (OR = 1,15; IC95%: 1,01; 1,31), cuando se compara con aquellos que estaban hasta 3 horas/día. De esa forma, se evidenció que tiempos elevados en comportamiento sedentario se mostraron factores de riesgo relevantes para la ocurrencia de multimorbilidad y sus patrones en ancianos.

Knowledge, attitudes, and practices of primary health care professionals in coping with COVID-19 in Brazil: a cross-sectional study.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic has posed challenges to healthcare professionals, who needed to quickly adjust impacts on their work processes. Primary health care has become key to fighting the pandemic, as most mild cases seek primary care services as their point of first contact. Objectives: To ascertain the knowledge, attitudes, and practices of health professionals working in primary health care in Brazil early in the COVID-19 pandemic. Methods: Cross-sectional study of a convenience sample. An online questionnaire was made available from May 1 through May 31, 2020. The sole criterion for inclusion was a response rate greater than 30 respondents per Brazilian state. Data were treated descriptively and statistically. Results: Overall, 293 responses were obtained, and the states of Paraná (n = 86), Mato do Grosso do Sul (n = 50) and São Paulo (n = 48) were included in the study. There was a predominance of female respondents (89.1%). Physical therapy (31.6%) and nursing (12.4%) were the most represented occupations. Respondents generally reported moderate knowledge (54.3%) and preparedness (57.6%), with daily information seeking (63.5%) in handbooks and technical guidance publications (89.6%). There was no statistically significant difference between states for the variables knowledge (p = 0.28) and preparedness (p = 0.19). Conclusions: The participating states showed similar, positive results regarding knowledge, attitudes, and practices. Previous experiences seem to generate cumulative knowledge; however, greater readiness in training professionals is needed in emergency situations.

Inactivation of the dorsolateral periaqueductal gray matter impairs the promoting influence of stress on fear memory during retrieval.

Exposure to stressful conditions induces long-lasting neurobiological changes in selected brain areas, which could be associated with the emergence of negative emotional responses. Moreover, the interaction of a stressful experience and the retrieval of an established fear memory trace enhance both fear expression and fear retention. Related to this, the stimulation of the dorsolateral part of the mesencephalic periaqueductal gray matter (dlPAG) prior to retrieval potentiates a fear memory trace previously acquired. Therefore, the question that arises is whether the dlPAG mediates the increased fear expression and fear retention after retrieval. Rats were subjected to a contextual fear conditioning paradigm using a single footshock, and 1 day later, rats were subjected to a stressful situation. As previously reported, there was an increase of freezing response only in those rodents that were re-exposed to the associated context at 1 and 5 days after stress exposure. Muscimol intra-dlPAG prior to the restraint event prevented such increase. Conversely, Muscimol intra-dlPAG infusion immediately after the stress experience had no effect on the resulting fear memory. When the neuroendocrine response to stress was explored, intra-dlPAG infusion of muscimol prior to stress decreased Fos expression in the paraventricular nucleus and serum corticosterone levels. Moreover, this treatment prevented the enhancement of the density of hippocampal "mature" spines associated with fear memory. In conclusion, the present results suggest that the dlPAG is a key neural site for the negative valence instruction necessary to modulate the promoting influence of stress on fear memory.

Olfactory instruction for fear: neural system analysis.

Different types of predator odors engage elements of the hypothalamic predator-responsive circuit, which has been largely investigated in studies using cat odor exposure. Studies using cat odor have led to detailed mapping of the neural sites involved in innate and contextual fear responses. Here, we reviewed three lines of work examining the dynamics of the neural systems that organize innate and learned fear responses to cat odor. In the first section, we explored the neural systems involved in innate fear responses and in the acquisition and expression of fear conditioning to cat odor, with a particular emphasis on the role of the dorsal premammillary nucleus (PMd) and the dorsolateral periaqueductal gray (PAGdl), which are key sites that influence innate fear and contextual conditioning. In the second section, we reviewed how chemical stimulation of the PMd and PAGdl may serve as a useful unconditioned stimulus in an olfactory fear conditioning paradigm; these experiments provide an interesting perspective for the understanding of learned fear to predator odor. Finally, in the third section, we explored the fact that neutral odors that acquire an aversive valence in a shock-paired conditioning paradigm may mimic predator odor and mobilize elements of the hypothalamic predator-responsive circuit.

Neuronal nitric-oxide synthase deficiency impairs the long-term memory of olfactory fear learning and increases odor generalization.

Experience-induced changes associated with odor learning are mediated by a number of signaling molecules, including nitric oxide (NO), which is predominantly synthesized by neuronal nitric oxide synthase (nNOS) in the brain. In the current study, we investigated the role of nNOS in the acquisition and retention of conditioned olfactory fear. Mice lacking nNOS received six training trials, each consisting of an odor-CS co-terminating with a foot shock-US. Mice showed reduced freezing responses to the trained odor 24 h and 7 d after training, compared to wild-type mice. Pretraining systemic injections of the NO donor, molsidomine, rescued fear retention in nNOS knockout mice. In wild-type mice, pretraining systemic injections of L-NAME, a nonspecific nNOS blocker, disrupted odor-CS fear retention in a dose-dependent manner. To evaluate whether NO signaling is involved in generalization of fear memories, nNOS knockout mice and wild-type mice receiving L-NAME were trained to one odor and tested with a series of similar odors. In both cases, we found increased generalization, as measured by increased freezing to similar, unpaired odors. Despite the impairment in fear memory retention and generalization, neither mice receiving injections of L-NAME nor nNOS knockout mice showed any deficits in either novel odor investigation time or odor habituation, suggesting intact olfactory perception and short-term memory olfactory learning. These results support a necessary role for neuronal NO signaling in the normal expression and generalization of olfactory conditioned fear.

Fos expression in the prefrontal cortex and mesencephalic dorsal raphe nucleus in lactating rats after social instigation

Females are often less aggressive than males, but they exhibit high levels of agonistic behavior against an intruder in the area of ​​the nest during lactation. This behavior is referred to as maternal aggression. In rats, maternal aggressive behavior occurs more often from postpartum day 3 (PPD 3) to PPD 12. Social instigation is an experimental protocol used to increase the levels of aggression that are typical of the species. In the present study we used social instigation to analyze the expression of a marker of neuronal activity, c-fos. Lactating rats on PPD 5, in the presence of their pups, were divided into four groups: (1) no social instigation and no aggressive behavior, (2) social instigation and no aggressive behavior, (3) no social instigation and aggressive behavior, and (4) social instigation and aggressive behavior. Sixty minutes after the aggression test we used immunohistochemistry to detect Fos in two brain regions, the ventral-orbital region of the prefrontal cortex (VO PFC) and dorsal raphe nucleus (DRN). Our results showed that rats with aggressive behavior that were provoked exhibited an increase in Fos expression in the VO PFC compared with the control group (i.e., no social instigation and no aggressive behavior). No change in Fos expression was found in the DRN. These results complement previous findings with microinjection of serotonin 5-hydroxytryptamine-1B receptor agonists into the same region, demonstrating that the VO PFC is an important region in the modulation of maternal aggressive behavior.

Fos expression in the prefrontal cortex and mesencephalic dorsal raphe nucleus in lactating rats after social instigation

Females are often less aggressive than males, but they exhibit high levels of agonistic behavior against an intruder in the area of ​​the nest during lactation. This behavior is referred to as maternal aggression. In rats, maternal aggressive behavior occurs more often from postpartum day 3 (PPD 3) to PPD 12. Social instigation is an experimental protocol used to increase the levels of aggression that are typical of the species. In the present study we used social instigation to analyze the expression of a marker of neuronal activity, c-fos. Lactating rats on PPD 5, in the presence of their pups, were divided into four groups: (1) no social instigation and no aggressive behavior, (2) social instigation and no aggressive behavior, (3) no social instigation and aggressive behavior, and (4) social instigation and aggressive behavior. Sixty minutes after the aggression test we used immunohistochemistry to detect Fos in two brain regions, the ventral-orbital region of the prefrontal cortex (VO PFC) and dorsal raphe nucleus (DRN). Our results showed that rats with aggressive behavior that were provoked exhibited an increase in Fos expression in the VO PFC compared with the control group (i.e., no social instigation and no aggressive behavior). No change in Fos expression was found in the DRN. These results complement previous findings with microinjection of serotonin 5-hydroxytryptamine-1B receptor agonists into the same region, demonstrating that the VO PFC is an important region in the modulation of maternal aggressive behavior.(AU)

The dorsolateral periaqueductal gray and its role in mediating fear learning to life threatening events.

The dorsolateral column of the periaqueductal gray (dlPAG) integrates aversive emotional experiences and represents an important site responding to life threatening situations, such as hypoxia, cardiac pain and predator threats. Previous studies have shown that the dorsal PAG also supports fear learning; and we have currently explored how the dlPAG influences associative learning. We have first shown that N-methyl-D-aspartate (NMDA) 100 pmol injection in the dlPAG works as a valuable unconditioned stimulus (US) for the acquisition of olfactory fear conditioning (OFC) using amyl acetate odor as conditioned stimulus (CS). Next, we revisited the ascending projections of the dlPAG to the thalamus and hypothalamus to reveal potential paths that could mediate associative learning during OFC. Accordingly, the most important ascending target of the dlPAG is the hypothalamic defensive circuit, and we were able to show that pharmacological inactivation using ß-adrenoceptor blockade of the dorsal premammillary nucleus, the main exit way for the hypothalamic defensive circuit to thalamo-cortical circuits involved in fear learning, impaired the acquisition of the OFC promoted by NMDA stimulation of the dlPAG. Moreover, our tracing study revealed multiple parallel paths from the dlPAG to several thalamic targets linked to cortical-hippocampal-amygdalar circuits involved in fear learning. Overall, the results point to a major role of the dlPAG in the mediation of aversive associative learning via ascending projections to the medial hypothalamic defensive circuit, and perhaps, to other thalamic targets, as well. These results provide interesting perspectives to understand how life threatening events impact on fear learning, and should be useful to understand pathological fear memory encoding in anxiety disorders.

Cholinergic modulation during acquisition of olfactory fear conditioning alters learning and stimulus generalization in mice.

We investigated the role of cholinergic neurotransmission in olfactory fear learning. Mice receiving pairings of odor and foot shock displayed fear to the trained odor the following day. Pretraining injections of the nicotinic antagonist mecamylamine had no effect on subsequent freezing, while the muscarinic antagonist scopolamine significantly reduced freezing. To test whether cholinergic manipulation affected fear generalization, mice were presented with odors similar to the trained odor. Generalization was increased following pretraining scopolamine, while the muscarinic agonist oxotremorine decreased generalization. These results suggest that muscarinic neurotransmission during the acquisition of olfactory association modulates both the strength and specificity of learning.

Acquisition of Pavlovian fear conditioning using ß-adrenoceptor activation of the dorsal premammillary nucleus as an unconditioned stimulus to mimic live predator-threat exposure.

In the present work, we sought to mimic the internal state changes in response to a predator threat by pharmacologically stimulating the brain circuit involved in mediating predator fear responses, and explored whether this stimulation would be a valuable unconditioned stimulus (US) in an olfactory fear conditioning paradigm (OFC). The dorsal premammillary nucleus (PMd) is a key brain structure in the neural processing of anti-predatory defensive behavior and has also been shown to mediate the acquisition and expression of anti-predatory contextual conditioning fear responses. Rats were conditioned by pairing the US, which was an intra-PMd microinjection of isoproterenol (ISO; ß-adrenoceptor agonist), with amyl acetate odor-the conditioned stimulus (CS). ISO (10 and 40 nmol) induced the acquisition of the OFC and the second-order association by activation of ß-1 receptors in the PMd. Furthermore, similar to what had been found for contextual conditioning to a predator threat, atenolol (ß-1 receptor antagonist) in the PMd also impaired the acquisition and expression of OFC promoted by ISO. Considering the strong glutamatergic projections from the PMd to the dorsal periaqueductal gray (dPAG), we tested how the glutamatergic blockade of the dPAG would interfere with the OFC induced by ISO. Accordingly, microinjections of NMDA receptor antagonist (AP5, 6 nmol) into the dPAG were able to block both the acquisition, and partially, the expression of the OFC. In conclusion, we have found that PMd ß-1 adrenergic stimulation is a good model to mimic predatory threat-induced internal state changes, and works as a US able to mobilize the same systems involved in the acquisition and expression of predator-related contextual conditioning.

Folic acid administration prevents ouabain-induced hyperlocomotion and alterations in oxidative stress markers in the rat brain.

OBJECTIVE: Bipolar disorder (BD) is a chronic, prevalent, and highly debilitating psychiatric illness. Folic acid has been shown to have antidepressant-like effects in preclinical and clinical studies and has also been suggested to play a role in BD. The present work investigates the therapeutic value of folic acid supplementation in a preclinical animal model of mania induced by ouabain. METHODS: Male Wistar rats were treated twice daily for seven days with folic acid (10, 50, and 100 mg/kg, p.o.) or the mood stabilizer lithium chloride (LiCl) (45 mg/kg, p.o.). One day after the last dose was given, the animals received an i.c.v. injection of ouabain (10 microM), a Na(+),K(+)-ATPase-inhibiting compound. Locomotor activity was assessed in the open-field test. Thiobarbituric acid-reactive substance (TBARS) levels, glutathione peroxidase (GPx), and glutathione reductase (GR) activities were measured in the cerebral cortex and hippocampus. RESULTS: Ouabain (10 microM, i.c.v.) significantly increased motor activity in the open-field test, and seven days of pretreatment with folic acid (50 mg/kg, p.o.) or LiCl (45 mg/kg, p.o.) completely prevented this effect. Ouabain treatment elicited lipid peroxidation (increased TBARS levels) and reduced GPx activity in the hippocampus. GR activity was decreased in the cerebral cortex and hippocampus. These effects were prevented by pretreatment with folic acid and LiCl. CONCLUSIONS: Our results show that folic acid, similarly to LiCl, produces a clear antimanic action and prevents the neurochemical alterations indicative of oxidative stress in an animal model of mania.

Role of beta-adrenergic receptors in the ventromedial prefrontal cortex during contextual fear extinction in rats.

It has been reported that stress-related activation of the noradrenergic system strengthens the formation of aversive memories and that beta-adrenergic receptors seem to be involved in this emotional memory processing. In this study, the effects of beta-adrenergic compounds on the extinction of contextual conditioned fear responses were evaluated. Rats were trained with footshock in a conditioning box. In the 3 days following the training, the animals were re-exposed to the apparatus and received either a single or repeated intraperitoneal injections of the beta-adrenergic antagonist propranolol, the beta-adrenergic agonist isoproterenol, or saline 30 min before (acquisition of extinction) or immediately after (consolidation of extinction) the extinction sessions. A drug-free session was performed on the last day. While repeated isoproterenol treatment facilitated the consolidation of contextual fear extinction, repeated propranolol administration impaired the acquisition and the consolidation of this process. Further, the role of ventromedial prefrontal cortex (vmPFC) in the extinction of contextual conditioned fear was tested with an immunohistochemistry assay. Our results show a reduction in Fos-protein expression between the first and the last extinction session. In a follow-up experiment, intra-vmPFC microinjection of isoproterenol before the first extinction session facilitated the extinction of contextual fear. This facilitation was antagonized by pre-treatment with atenolol, suggesting that this change is mediated by beta-1-adrenergic activity. Our results reinforce the role of the vmPFC in fear extinction mechanisms, suggesting that vmPFC-beta-1-adrenergic receptor activation underlies part of the facilitation of the fear extinction processes.

Sensing danger through the olfactory system: the role of the hypothalamic dorsal premammillary nucleus.

The dorsal premammillary nucleus (PMd) has a critical role on the expression of defensive responses to predator odor. Anatomical evidence suggests that the PMd should also modulate memory processing through a projecting branch to the anterior thalamus. By using a pharmacological blockade of the PMd with the NMDA-receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5), we were able to confirm its role in the expression of unconditioned defensive responses, and further revealed that the nucleus is also involved in influencing associative mechanisms linking predatory threats to the related context. We have also tested whether olfactory fear conditioning, using coffee odor as CS, would be useful to model predator odor. Similar to cat odor, shock-paired coffee odor produced robust defensive behavior during exposure to the odor and to the associated context. Shock-paired coffee odor also up-regulated Fos expression in the PMd, and, as with cat odor, we showed that this nucleus is involved in the conditioned defensive responses to the shock-paired coffee odor and the contextual responses to the associated environment.