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Affiliative tactile interactions buffer social mammals against neurobiological and behavioral effects of stress. The aim of the present study was to investigate the cutaneous mechanisms underlying such beneficial consequences of touch by determining whether daily stroking, specifically targeted to activate a velocity/force tuned class of low-threshold c-fiber mechanoreceptor (CLTM), confers resilience against established markers of chronic unpredictable mild stress (CMS). Adult male Sprague Dawley rats were exposed to two weeks of CMS. Throughout the CMS protocol, some rats were stroked daily, either at CLTM optimal velocity (5cm/s) or outside the CLTM optimal range (30cm/s). A third CMS exposed group did not receive any tactile stimulation. The effect of CMS on serum corticosterone levels, anxiety- and depressive-like behaviors in these three groups was assessed in comparison to a control group of non-CMS exposed rats. While stroking did not mitigate the effects of CMS on body weight gain, CLTM optimal velocity stroking did significantly reduce CMS induced elevations in corticosterone following an acute forced-swim. Rats receiving CLTM optimal stroking also showed significantly fewer anxiety-like behaviors (elevated plus-maze) than the other CMS exposed rats. In terms of depressive-like behavior, while the same velocity specific resilience was observed in a forced-swim test (FST) and social interaction test both groups of stroked rats spent significantly less time interacting than control rats, though they also spent significantly less time in the corner than non-stroked CMS rats. Together, these findings support the theory CLTMs play a functional role in regulating the physiological condition of the body.

Modern lifestyle and adversities such as the COVID-19 pandemic pose challenges for our physical and mental health. Hence, it is of the utmost importance to identify mechanisms by which we can improve resilience to stress and quickly adapt to adversity. While there are several factors that improve stress resilience, social behavior—primarily in the form of social touch—is especially vital. This article provides an overview of how the somatosensory system plays a key role in translating the socio-emotional information of social touch into active coping with stress. Important future directions include evaluating in humans whether stress resilience can be modulated through the stimulation of low-threshold C-fiber mechanoreceptors and using this technology in the prevention of stress-related neuropsychiatric disorders such as major depressive disorder. © 2021 Elsevier Ltd

Memory and GABAergic activity in the hippocampus of stressed rats improve after n-3 polyunsaturated fatty acid (PUFA) supplementation. On the other hand, cannabinoid receptor type 1 (CB1) strongly regulates inhibitory neurotransmission in the hippocampus. Speculation about a possible relation between stress, endocannabinoids, and PUFAs. Here, we examined whether the effects of PUFAs on memory of chronically stressed rats depends on pharmacological manipulation of CB1 receptors. Male Sprague-Dawley rats were orally supplemented with n-3 (fish oil) or n-6 (primrose oil) PUFAs during chronic restraint stress (CRS) protocol (6 h/day; 21 days). First, we studied if the expression of CB1 receptors in the hippocampus may be affected by CRS and PUFAs supplementation by real-time PCR and immunofluorescence. CRS up-regulated the CB1 expression compared with the non-stressed rats, while only n-3 PUFAs countered this effect. Memory was evaluated in the Morris water maze. Stressed rats were co-treated with PUFAs and/or modulators of CB1 receptor (AM251, antagonist, 0.3 mg/kg/day; WIN55,212-2, agonist, 0.5 mg/kg/day) by intraperitoneal injections. Memory improved in the stressed rats that were treated with AM251 and/or n-3 PUFAs. Supplementation with n-6 PUFAs did not affect memory of stressed rats, but co-treatment with AM251 improved it, while co-treatment with WIN55,212-2 did not affect memory. Our results demonstrate that activity of the CB1 receptors may modulate the effects of PUFAs on memory of stressed rats. This study suggests that endocannabinoids and PUFAs can both become a singular system by being self-regulated in limbic areas, so they control the effects of stress on the brain.

In modern lifestyle, stress and Western diets are two major environmental risk factors involved in the etiology of neuropsychiatric disorders. Lifelong interactions between stress, Western diets, and how they can affect brain physiology, remain unknown. A possible relation between dietary long chain polyunsaturated fatty acids (PUFA), endocannabinoids, and stress is proposed. This review suggests that both Western diets and negative stress or distress increase n-6/n-3 PUFA ratio in the phospholipids of the plasma membrane in neurons, allowing an over-activation of the endocannabinoid system in the limbic areas that control emotions. As a consequence, an excitatory/inhibitory imbalance is induced, which may affect the ability to synchronize brain areas involved in the control of stress responses. These alterations increase vulnerability to neuropsychiatric disorders. Accordingly, dietary intake of n-3 PUFA would counter the effects of stress on the brain of stressed subjects. In conclusion, this article proposes that PUFA, endocannabinoids, and stress form a unique system which is self-regulated in limbic areas which in turn controls the effects of stress on the brain throughout a lifetime.

Resilience to stress is the ability to quickly adapt to adversity. There is evidence that exposure to prolonged stress triggers neuroinflammation what produces individual differences in stress vulnerability. However, the relationship between stress resilience, neuroinflammation, and depressive-like behaviors remains unknown. The aim of this study was to analyze the long-term effects of social defeat stress (SDS) on neuroinflammation in the hippocampus and depressive-like behaviors. Male rats were subjected to the SDS paradigm. Social interaction was analyzed 1 and 2 weeks after ending the SDS to determine which animals were susceptible or resilient to stress. Neuroinflammation markers glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, and elevated membrane permeability in astrocytes and microglia, as well as depressive-like behaviors in the sucrose preference test and forced swim test were evaluated in all rats. One week after SDS, resilient rats increased their sucrose preference, and time spent in the floating behavior decreased in the forced swim test compared to susceptible rats. Surprisingly, resilient rats became susceptible to stress, and presented neuroinflammation 2 weeks after SDS. These findings suggest that SDS-induced hippocampal neuroinflammation persists in post-stress stages, regardless of whether rats were initially resilient or not. Our study opens a new approach to understanding the neurobiology of stress resilience.

The concept of stress is a fundamental piece to understand how organisms can adapt to the demands produced by a continuously changing environment. However, modern lifestyle subjects humans to high levels of negative stress or distress, which increases the prevalence of mental illnesses. Definitely, stress has become the pandemic of the 21st century, a fact that demands a great intellectual effort from scientists to understand the neurobiology of stress. This review proposes an innovative point of view to understand that mood disorders and dementia have a common etiology in a stressful environment. We propose that distress produces sensory deprivation, and this interferes with the connection between the brain and the environment in which the subject lives. The auditory system can serve as an example to understand this idea. In this sense, distress impairs the auditory system and induces hearing loss or presbycusis at an early age; this can increase the cognitive load in stressed people, which can stimulate the development of dementia in them. On the other hand, distress impairs the auditory system and increases the excitability of the amygdala, a limbic structure involved in the emotional processing of sounds. A consequence of these alterations could be the increase in the persistence of auditory fear memory, which could increase the development of mood disorders. Finally, it is important to emphasize that stress is an evolutionary issue that is necessary to understand the mental health of humans in these modern times. This article is a contribution to this discussion and will provide insights into the origin of stress-related neuropsychiatric disorders.

Alteration in social behavior is one of the most debilitating symptoms of major depression, a stress related mental illness. Social behavior is modulated by the reward system, and gamma oscillations in the nucleus accumbens seem to be associated with reward processing. In this scenario, the role of gamma oscillations in depression remains unknown. We hypothesized that gamma oscillations in the rat nucleus accumbens are sensitive to the effects of social distress. One group of male Sprague-Dawley rats were exposed to chronic social defeat stress while the other group was left undisturbed (control group). Afterward, a microelectrode array was implanted in the nucleus accumbens of all animals. Local field potential activity was acquired using a wireless recording system. In an open field chamber, where implanted rats were placed by themselves for a non-social interaction condition, followed by introducing another unfamiliar rat, creating a social interaction condition, where the implanted rats interacted freely and continuously with the unfamiliar conspecific in a natural-like manner. We found that the high-gamma band power in the nucleus accumbens of non-stressed rats was higher during the social interaction compared to a non-social interaction condition. Conversely, we did not find significant differences at this level in the stressed rats when comparing the social interaction- and non-social interaction condition. These findings suggest that high-gamma oscillations in the nucleus accumbens are involved in social behavior. Furthermore, alterations at this level could be an electrophysiological signature of the effect of chronic social stress on reward processing.

While chronic stress induces dendritic atrophy in the hippocampus and impairs learning and memory, supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) is known to improve learning and memory of control rats. Whether n-3 PUFA supplementation improves dendritic morphology, synaptic transmission, and memory of chronically stressed rats remains unknown. In this work, we randomly assigned male Sprague-Dawley rats in four experimental groups: two unsupplemented groups, control and stress, and two supplemented groups with n-3 PUFA (DHA and EPA mix), control + n-3 PUFA and stress + n-3 PUFA. Dendritic morphology and synaptic transmission in the hippocampus were evaluated by Golgi stain and patch-clamp tools, respectively. The Y-maze and Morris water maze were used to analyze the effects of chronic stress on memory. Supplementation with n-3 PUFA improved dendritic architecture and restored the frequency of inhibitory post-synaptic currents of hippocampal pyramidal neurons of rats from stress group. In addition, n-3 PUFA supplementation improved spatial memory. Our results demonstrate that n-3 PUFA supplementation had three beneficial effects on stressed rats: prevented or compensated dendritic atrophy in CA3; restored the probability of GABA release in CA1; and improved spatial memory. We argue that n-3 PUFA supplementation can be used in treating stress-related psychiatric disorders such as depression and anxiety.

Research in programming has focused in the study of stimuli that affect sensitive periods of development such as prenatal and neonatal stage. We previously showed that exposure to estradiol valerate to female rats during the first 12 h of life increased catecholamine content in ventromedial-arcuatus hypothalamus of the adult rat. However, changes in others dopaminergic circuits have not been studied. The purpose of this work was to determine the neurotransmitters changes induced by neonatal estradiol valerate (0.1 mg/50 μl s. c. per rat) administration on nigrostriatal pathway of adult female rats. Sesame oil (50 μl s. c. per rat) was administered in a control parallel group. EV-1 adult rats presented effective markers of long-term estrogenization as decreased serum levels of progesterone and a reduction in the size of estrogen-sensitive organs. In the brain, neonatal estradiol valerate administration led to a significant increase in dopamine content in striatum, substantia nigra and ventral tegmental area. With respect to the contents of dopamine metabolites, only 3-methoxytyramine content increased in substantia nigra and ventral tegmental area. In addition, the content of noradrenaline increased only in striatum. Interestingly, estrogenized rats lacked locomotor activity induced by acute dose of amphetamine (1 mg/kg i. p.). Altogether, these results show that neonatal exposure to estradiol valerate permanently modified the content of monoamine neurotransmitters in nigrostriatal pathway and amphetamine-induced locomotor activity of adult female rats. This might imply that estrogenized rats could have changes in the expression of key proteins in dopaminergic regulation, as tyrosine hydroxylase and dopamine transporter.

Chronic stress impairs auditory attention in rats and monoamines regulate neurotransmission in the primary auditory cortex (A1), a brain area that modulates auditory attention. In this context, we hypothesized that norepinephrine (NE) levels in A1 correlate with the auditory attention performance of chronically stressed rats. The first objective of this research was to evaluate whether chronic stress affects monoamines levels in A1. Male Sprague–Dawley rats were subjected to chronic stress (restraint stress) and monoamines levels were measured by high performance liquid chromatographer (HPLC)-electrochemical detection. Chronically stressed rats had lower levels of NE in A1 than did controls, while chronic stress did not affect serotonin (5-HT) and dopamine (DA) levels. The second aim was to determine the effects of reboxetine (a selective inhibitor of NE reuptake) on auditory attention and NE levels in A1. Rats were trained to discriminate between two tones of different frequencies in a two-alternative choice task (2-ACT), a behavioral paradigm to study auditory attention in rats. Trained animals that reached a performance of ≥80% correct trials in the 2-ACT were randomly assigned to control and stress experimental groups. To analyze the effects of chronic stress on the auditory task, trained rats of both groups were subjected to 50 2-ACT trials 1 day before and 1 day after of the chronic stress period. A difference score (DS) was determined by subtracting the number of correct trials after the chronic stress protocol from those before. An unexpected result was that vehicle-treated control rats and vehicle-treated chronically stressed rats had similar performances in the attentional task, suggesting that repeated injections with vehicle were stressful for control animals and deteriorated their auditory attention. In this regard, both auditory attention and NE levels in A1 were higher in chronically stressed rats treated with reboxetine than in vehicle-treated animals. These results indicate that NE has a key role in A1 and attention of stressed rats during tone discrimination.

Chronic stress affects brain areas involved in learning and emotional responses. Although most studies have concentrated on the effect of stress on limbic-related brain structures, in this study we investigated whether chronic stress might induce impairments in diencephalic structures associated with limbic components of the stress response. Specifically, we analyzed the effect of chronic immobilization stress on the expression of sympathetic markers in the rat epithalamic pineal gland by immunohistochemistry and western blot, whereas the plasma melatonin concentration was determined by radioimmunoassay. We found that chronic stress decreased the expression of three sympathetic markers in the pineal gland, tyrosine hydroxylase, the p75 neurotrophin receptor and alpha-tubulin, while the same treatment did not affect the expression of the non-specific sympathetic markers Erk1 and Erk2, and glyceraldehyde-3-phosphate dehydrogenase. Furthermore, these results were correlated with a significant increase in plasma melatonin concentration in stressed rats when compared with control animals. Our findings indicate that stress may impair pineal sympathetic inputs, leading to an abnormal melatonin release that may contribute to environmental maladaptation. In addition, we propose that the pineal gland is a target of glucocorticoid damage during stress.

Stress leads to secretion of the adrenal steroid hormone corticosterone (CORT). The aim of this study was to determine the effects of chronic CORT administration on auditory and visual fear conditioning. Male Sprague-Dawley rats received CORT (400 mg/ml) in their drinking water for 10 consecutive days; this treatment induces stress levels of serum CORT. CORT impaired fear conditioning (F((1,28)) = 11.52, p 0.01) and extinction (F((1,28)) = 4.86, p 0.05) of auditory fear learning, but did not affect visual fear conditioning. In addition, we analyzed the CORT effects on the neuronal morphology of the inferior colliculus (flat neurons, auditory mesencephalon, a key brain area for auditory processing) and superior colliculus (wide-field neurons, related to visual processing) by Golgi stain. CORT decreased dendritic arborization of inferior colliculus neurons by approximately 50%, but did not affect superior colliculus neurons. Thus, CORT had more deleterious effects on the auditory fear processing than the visual system in the brain.

The foetal brain is highly susceptible to stress in late pregnancy, with lifelong effects of stress on physiology and behaviour. The present study aimed to determine the physiological and behavioural effects of prenatal stress during the prepubertal period of female and male rats. We subjected pregnant Sprague-Dawley rats to a restraint stress protocol from gestational day 14 to 21, a critical period for foetal brain susceptibility to stress effects. Male and female offspring were subsequently assessed at postnatal day 24 for anxiety- and depressive-like behaviours, as well as spontaneous social interaction. We also assessed maternal behaviours and 2 stress markers: basal vs acute-evoked stress levels of serum corticosterone and body weight gain. Prenatal stress did not affect the maternal behaviour, whereas both female and male offspring had higher body weight gain. On the other hand, lower levels of corticosterone after acute stress stimulation, as well as anxiety- and depressive-like behaviours, were only evident in stressed males compared to control males. These results suggest that prenatal stress induced sex-specific effects on hypothalamic-pituitary-adrenal (HPA) axis activity and on behaviour during prepuberty. The HPA axis of prenatally stressed male rats was less active compared to control males, and they were also more anxious and experienced depressive-like behaviours. These results are useful with respect to studying the neurobiological basis of childhood depression at a preclinical level.

The present study aimed to identify morphological correlates of environment-induced changes at excitatory synapses of the primary auditory cortex (A1). We used the Golgi-Cox stain technique to compare pyramidal cells dendritic properties of Sprague-Dawley rats exposed to different environmental manipulations. Sholl analysis, dendritic length measures, and spine density counts were used to monitor the effects of sensory deafness and an auditory version of environmental enrichment (EE). We found that deafness decreased apical dendritic length leaving basal dendritic length unchanged, whereas EE selectively increased basal dendritic length without changing apical dendritic length. On the contrary, deafness decreased while EE increased spine density in both basal and apical dendrites of A1 Layer 2/3 (LII/III) neurons. To determine whether stress contributed to the observed morphological changes in A1, we studied neural morphology in a restraint-induced model that lacked behaviorally relevant acoustic cues. We found that stress selectively decreased apical dendritic length in the auditory but not in the visual primary cortex. Similar to the acoustic manipulation, stress-induced changes in dendritic length possessed a layer-specific pattern displaying LII/III neurons from stressed animals with normal apical dendrites but shorter basal dendrites, while infragranular neurons (Layers V and VI) displayed shorter apical dendrites but normal basal dendrites. The same treatment did not induce similar changes in the visual cortex, demonstrating that the auditory cortex is an exquisitely sensitive target of neocortical plasticity, and that prolonged exposure to different acoustic as well as emotional environmental manipulation may produce specific changes in dendritic shape and spine density.

Organophosphate pesticides have been classically described as inhibitors of acetylcholinesterase (AChE) activity in insects and invertebrates. However, there is now more evidence supporting the hypothesis that these compounds also act through noncholinergic pathways, especially those related to cognitive processes. The enzyme acylpeptide hydrolase was identified as a new target for organophosphate pesticides. This enzyme is more sensitive than AChE to some organophosphates (OP), including dichlorvos, which is the parent compound for metrifonate, a therapeutic agent used in the treatment of cognitive impairment associated to Alzheimer's disease. Therefore, there is some doubt as to whether the mechanism of action of this drug is mediated by a potentiation of cholinergic transmission. However, the direct action of acylpeptide hydrolase in cognitive processes and the physiological and molecular mechanisms underlying subacute exposure to OP have yet to be demonstrated. This review deals with evidence demonstrating the existence of mechanisms of actions of OP, which are independent of cholinergic pathway potentiation and which have an effect on cognitive processes. In addition, the possible participation of the enzyme acylpeptide hydrolase in these processes is also discussed. Finally, the possibility of using this enzyme activity as a new biomarker for exposure to OP is considered.

Induction of status epilepticus (SE) with kainic acid results in a large reorganization of neuronal brain circuits, a phenomenon that has been studied primarily in the hippocampus. The neurotrophin BDNF, by acting through its receptor TrkB, has been implicated in such reorganization. In the present work we investigated, by Western blot and immunohistochemistry, whether regional changes of TrkB expression within the rat brain cortex are correlated with altered neuronal morphology and/or with apoptotic cell death. We found that the full-length TrkB protein decreased within the cortex when measured 24 h to 1 week after induction of SE. Analysis by immunohistochemistry revealed that TrkB staining diminished within layer V of the retrosplenial granular b (RSGb) and motor cortices, but not within the auditory cortex. In layer II/III, differential changes were also observed: TrkB decreased in the motor cortex, did not change within the RSGb but increased within the auditory cortex. Reduced TrkB was associated with dendritic atrophy and decreased spine density in pyramidal neurons within layer V of the RSGb. No correlation was observed between regional and cellular changes of TrkB protein and apoptosis, measured by the TdT-mediated dUTP nick end labeling (TUNEL) method. The global decrease of TrkB within the neocortex and the associated dendritic atrophy may counteract seizure propagation in the epileptic brain but may also underlie cognitive impairment after seizures.

Chronic stress affects brain areas involved in learning and emotional responses. These alterations have been related with the development of cognitive deficits in major depression. Moreover, stress induces deleterious actions on the epithalamic pineal organ, a gland involved in a wide range of physiological functions. The aim of this study was to investigate whether the stress effects on the pineal gland are related with changes in the expression of neurotrophic factors and cell adhesion molecules. Using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot, we analyzed the effect of chronic immobilization stress on the BDNF mRNA and integrin alpha5 expression in the rat pineal gland. We found that BDNF is produced in situ in the pineal gland. Chronic immobilization stress induced upregulation of BDNF mRNA and integrin alpha5 expression in the rat pineal gland but did not produce changes in beta-actin mRNA or in GAPDH expression. Stressed animals also evidenced an increase in anxiety-like behavior and acute gastric lesions. These results suggest that BDNF and integrin alpha5 may have a counteracting effect to the deleterious actions of immobilization stress on functionally stimulated pinealocytes. Furthermore, this study proposes that the pineal gland may be a target of glucocorticoid damage during stress.

We report the establishment of continuously growing cell lines from spinal cords of normal and trisomy 16 fetal mice. We show that both cell lines, named M4b (derived from a normal animal) and MTh (trisomic) possess neurological markers by immunohistochemistry (neuron specific enolase, synaptophysin, microtubule associated protein-2 [MAP-2], and choline acetyltransferase) and lack glial traits (glial fibrillary acidic protein and S100). MTh cells were shown to overexpress mRNA of Cu/Zn superoxide dismutase, whose gene is present in autosome 16. We also studied intracellular Ca2+ signals ([Ca2+]i) induced by different agonists in Indo-1 loaded cells. Basal [Ca2+]i was significantly higher in MTh cells compared to M4b cells. Glutamate (200 microM) and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACDP) (100 microM) induced rapid, transient increases in [Ca2+]i in M4b and MTh cells, indicating the presence of glutamatergic metabotropic receptors. N-methyl-D-aspartate (NMDA) and kainate, but not alpha-amino-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), produced [Ca2+)]i rises in both cell types. MTh cells exhibited faster time-dependent decay phase kinetics in glutamate-induced responses compared to M4b cells. Nicotine induced a transient increase in [Ca2+]i in M4b and MTh cells, with significantly greater amplitudes in the latter compared to the former. Further, both cell types responded to noradrenaline. Finally, we examined cholinergic function in both cell lines and found no significant differences in the [3H]-choline uptake, but fractional acetylcholine release induced by either K+, glutamate or nicotine was significantly higher in MTh cells. These results show that M4b and MTh cells have neuronal characteristics and the MTh line shows differences which could be related to neuronal pathophysiology in Down's syndrome.

The mechanism of copper (Cu) neurotoxicity was studied in the RCSN-3 neuronal dopaminergic cell line, derived from substantia nigra of an adult rat. The formation of a Cu-dopamine complex was accompanied by oxidation of dopamine to aminochrome. We found that the Cu-dopamine complex mediates the uptake of (64)CuSO(4) into the Raul Caviedes substantia nigra-clone 3 (RCSN3) cells, and it is inhibited by the addition of excess dopamine (2 m M) (63%, p < 0.001) and nomifensine (2 microM) (77%, p < 0.001). Copper sulfate (1 m M) alone was not toxic to RCSN-3 cells, but was when combined with dopamine or with dicoumarol (95% toxicity; p < 0.001) which inhibits DPNH and TPNH (DT)-diaphorase. Electron spin resonance (ESR) spectrum of the 5,5-dimethylpyrroline-N-oxide (DMPO) spin trap adducts showed the presence of a C-centered radical when incubating cells with dopamine, CuSO(4) and dicoumarol. A decrease in the expression of CuZn-superoxide dismutase and glutathione peroxidase mRNA was observed when RCSN-3 cells were treated with CuSO(4), dopamine, or CuSO(4) and dopamine. However, the mRNA expression of glutathione peroxidase remained at control levels when the cells were treated with CuSO(4), dopamine and dicoumarol. The regulation of catalase was different since all the treatments with CuSO(4) increased the expression of catalase mRNA. Our results suggest that copper neurotoxicity is dependent on: (i) the formation of Cu-dopamine complexes with concomitant dopamine oxidation to aminochrome; (ii) dopamine-dependent Cu uptake; and (iii) one-electron reduction of aminochrome.

The prelimbic cortex and amygdala regulate the extinction of conditioned fear and anxiety, respectively. In adult rats, chronic stress affects the dendritic morphology of these brain areas, slowing extinction of learned fear and enhancing anxiety. The aim of this study was to determine whether rats subjected to chronic stress in adolescence show changes in learned fear, anxiety, and synaptic transmission in the prelimbic cortex during adulthood. Male Sprague Dawley rats were subjected to seven days of restraint stress on postnatal day forty-two (PND 42, adolescence). Afterward, the fear-conditioning paradigm was used to study conditioned fear extinction. Anxiety-like behavior was measured one day (PND 50) and twenty-one days (PND 70, adulthood) after stress using the elevated-plus maze and dark-light box tests, respectively. With another set of rats, excitatory synaptic transmission was analyzed with slices of the prelimbic cortex. Rats that had been stressed during adolescence and adulthood had higher anxiety-like behavior levels than did controls, while stress-induced slowing of learned fear extinction in adolescence was reversed during adulthood. As well, the field excitatory postsynaptic potentials of stressed adolescent rats had significantly lower amplitudes than those of controls, although the amplitudes were higher in adulthood. Our results demonstrate that short-term stress in adolescence induces strong effects on excitatory synaptic transmission in the prelimbic cortex and extinction of learned fear, where the effect of stress on anxiety is more persistent than on the extinction of learned fear. These data contribute to the understanding of stress neurobiology.

Chronic stress leads to secretion of the adrenal steroid hormone corticosterone, inducing hippocampal atrophy and dendritic hypertrophy in the rat amygdala. Both alterations have been correlated with memory impairment and increased anxiety. Supplementation with ω-3 fatty acids improves memory and learning in rats. The aim of this study was to evaluate the effects of ω-3 supplementation on learning and major biological and behavioral stress markers. Male Sprague–Dawley rats were randomly assigned to three experimental groups: 1) Control, 2) Vehicle, animals supplemented with water, and 3) ω-3, rats supplemented with ω-3 (100 mg of DHA+25 mg of EPA). Each experimental group was divided into two subgroups: one of which was not subjected to stress while the other was subjected to a restraint stress paradigm. Afterwards, learning was analyzed by avoidance conditioning. As well, plasma corticosterone levels and anxiety were evaluated as stress markers, respectively by ELISA and the plus-maze test. Restraint stress impaired learning and increased both corticosterone levels and the number of entries into the open-arm (elevated plus-maze). These alterations were prevented by ω-3 supplementation. Thus, our results demonstrate that ω-3 supplementation had two beneficial effects on the stressed rats, a strong anti-stress effect and improved learning.

Chronic stress induces dendritic atrophy in the rat primary auditory cortex (A1), a key brain area for auditory attention. The aim of this study was to determine whether repeated restraint stress affects auditory attention and synaptic transmission in A1. Male Sprague-Dawley rats were trained in a two-alternative choice task (2-ACT), a behavioral paradigm to study auditory attention in rats. Trained animals that reached a performance over 80% of correct trials in the 2-ACT were randomly assigned to control and restraint stress experimental groups. To analyze the effects of restraint stress on the auditory attention, trained rats of both groups were subjected to 50 2-ACT trials one day before and one day after of the stress period. A difference score was determined by subtracting the number of correct trials after from those before the stress protocol. Another set of rats was used to study the synaptic transmission in A1. Restraint stress decreased the number of correct trials by 28% compared to the performance of control animals (p0.001). Furthermore, stress reduced the frequency of spontaneous inhibitory postsynaptic currents (sIPSC) and miniature IPSC in A1, whereas glutamatergic efficacy was not affected. Our results demonstrate that restraint stress decreased auditory attention and GABAergic synaptic efficacy in A1.

Stress is a complex biological reaction common to all living organisms that allows them to adapt to their environments. Chronic stress alters the dendritic architecture and function of the limbic brain areas that affect memory, learning, and emotional processing. This review summarizes our research about chronic stress effects on the auditory system, providing the details of how we developed the main hypotheses that currently guide our research. The aims of our studies are to (1) determine how chronic stress impairs the dendritic morphology of the main nuclei of the rat auditory system, the inferior colliculus (auditory mesencephalon), the medial geniculate nucleus (auditory thalamus), and the primary auditory cortex; (2) correlate the anatomic alterations with the impairments of auditory fear learning; and (3) investigate how the stress-induced alterations in the rat limbic system may spread to nonlimbic areas, affecting specific sensory system, such as the auditory and olfactory systems, and complex cognitive functions, such as auditory attention. Finally, this article gives a new evolutionary approach to understanding the neurobiology of stress and the stress-related disorders.

Drying kinetics of quinoa-supplemented feed for laboratory rats during processing at 50, 60, 70, 80 and 90ºC was studied and modeled in this work. Desorption isotherm was obtained at 60ºC giving a monolayer moisture content of 0.04 g water/g d.m. The experimental drying curves showed that drying process took place only in the falling rate period. Several thin-layer drying equations available in the literature were evaluated based on determination coefficient (r²), sum squared errors (SSE) and Chi-square (χ2) statisticals. In comparison to the experimental moisture values, the values estimated with the Logarithmic model gave the best fit quality (r² >0.994, SSE < 0.00015 and χ2 < 0.00018), showing this equation could predict very accurately the drying time of rat feed under the operative conditions applied.

It has been postulated that chronic administration of antidepressant drugs induces delayed structural and molecular adaptations at glutamatergic forebrain synapses that might underlie mood improvement. To gain further insight into these changes in the cerebral cortex, rats were treated with fluoxetine (flx) for 4 weeks. These animals showed decreased anxiety and learned helplessness. N-methyl- d -aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor subunit levels (NR1, NR2A, NR2B, GluR1 and GluR2) were analysed in the forebrain by both western blot of homogenates and immunohistochemistry. Both methods demonstrated an upregulation of NR2A, GluR1 and GluR2 that was especially significant in the retrosplenial granular b cortex (RSGb). However, when analysing subunit content in postsynaptic densities and synaptic membranes, we found increases of NR2A and GluR2 but not GluR1. Instead, GluR1 was augmented in a microsomal fraction containing intracellular membranes. NR1 and GluR2 were co-immunoprecipitated from postsynaptic densities and synaptic membranes. In the immunoprecipitates, NR2A was increased while GluR1 was decreased supporting a change in receptor stoichiometry. The changes of subunit levels were associated with an upregulation of dendritic spine density and of large, mushroom-type spines. These molecular and structural adaptations might be involved in neuronal network stabilization following long-term flx treatment.

Chronic stress induces dendritic atrophy in the inferior colliculus (IC, auditory mesencephalon) and impairs auditory avoidance conditioning. The aim of this study was to determine in Golgi preparations and in cued fear conditioning whether stress affects other auditory components, like the thalamic medial geniculate nucleus (MG) or the posterior thalamic nucleus (PO), in Sprague-Dawley rats. Chronic restraint stress produced a significant dendritic atrophy in the MG (stress: 407+/-55 microm; control: 808+/-120 microm; p

Chronic stress affects brain areas involved in learning and emotional responses. These alterations have been related with the development of cognitive deficits in major depression. The aim of this study was to determine the effect of chronic immobilization stress on the auditory and visual mesencephalic regions in the rat brain. We analyzed in Golgi preparations whether stress impairs the neuronal morphology of the inferior (auditory processing) and superior colliculi (visual processing). Afterward, we examined the effect of stress on acoustic and visual conditioning using an avoidance conditioning test. We found that stress induced dendritic atrophy in inferior colliculus neurons and did not affect neuronal morphology in the superior colliculus. Furthermore, stressed rats showed a stronger impairment in acoustic conditioning than in visual conditioning. Fifteen days post-stress the inferior colliculus neurons completely restored their dendritic structure, showing a high level of neural plasticity that is correlated with an improvement in acoustic learning. These results suggest that chronic stress has more deleterious effects in the subcortical auditory system than in the visual system and may affect the aversive system and fear-like behaviors. Our study opens a new approach to understand the pathophysiology of stress and stress-related disorders such as major depression.

Monoamine oxidase-A (MAO-A) [amiflamine (AMF) and 4-methylthioamphetamine (MTA)] and MAO-B (L-deprenyl) inhibitors were found to be cytotoxic in a concentration-dependent manner for RCHT cells derived from adult rat hypothalamus. The cytotoxic effects were increased when the inhibitors were co-incubated with dicoumarol and especially with 25 micro M AMF+100 micro M dicoumarol (2.5-fold; P0.001). The treatment of RCHT cells solely with AMF induced a marked decrease in the expression of DT-diaphorase mRNA.

We report the establishment of continuously growing cell lines from spinal cords of normal and trisomy 16 fetal mice. We show that both cell lines, named M4b (derived from a normal animal) and MTh (trisomic) possess neurological markers by immunohistochemistry (neuron specific enolase, synaptophysin, microtubule associated protein-2 [MAP-2], and choline acetyltransferase) and lack glial traits (glial fibrillary acidic protein and S100). MTh cells were shown to overexpress mRNA of Cu/Zn superoxide dismutase, whose gene is present in autosome 16. We also studied intracellular Ca2+ signals ([Ca2+]i) induced by different agonists in Indo-1 loaded cells. Basal [Ca2+]i was significantly higher in MTh cells compared to M4b cells. Glutamate (200 microM) and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACDP) (100 microM) induced rapid, transient increases in [Ca2+]i in M4b and MTh cells, indicating the presence of glutamatergic metabotropic receptors. N-methyl-D-aspartate (NMDA) and kainate, but not alpha-amino-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), produced [Ca2+)]i rises in both cell types. MTh cells exhibited faster time-dependent decay phase kinetics in glutamate-induced responses compared to M4b cells. Nicotine induced a transient increase in [Ca2+]i in M4b and MTh cells, with significantly greater amplitudes in the latter compared to the former. Further, both cell types responded to noradrenaline. Finally, we examined cholinergic function in both cell lines and found no significant differences in the [3H]-choline uptake, but fractional acetylcholine release induced by either K+, glutamate or nicotine was significantly higher in MTh cells. These results show that M4b and MTh cells have neuronal characteristics and the MTh line shows differences which could be related to neuronal pathophysiology in Down's syndrome.

The endogenous dopamine-derived neurotoxin sal- solinol was found to decrease survival in the dopami- nergic neuronal cell line RCSN-3, derived from adult rat substantia nigra in a concentration-dependent manner (208 mM salsolinol induced a 50% survival de- crease). Incubation of RCSN-3 cells with 100 mM dicou- marol and salsolinol significantly decreased cell survival by 2.5-fold (P < 0.001), contrasting with a negligible effect on RCHT cells, which exhibited nearly a 5-fold lower nomifensine-insensitive dopa- mine uptake. The levels of catalase and glutathione peroxidase mRNA were decreased when RCSN-3 cells were treated with 100 mM salsolinol alone or in the presence of 100 mM dicoumarol. In vitro oxidation of salsolinol to o-quinone catalyzed by lactoperoxidase gave the quinone methide and 1,2-dihydro-1-methyl- 6,7-isoquinoline diol as final products of salsolinol ox- idation as determined by NMR analysis. Evidence of the formation of salsolinol o-semiquinone radical has been provided by ESR studies during one-electron ox- idation of salsolinol catalyzed by lactoperoxidase. © 2001 Academic Press

Human glutathione transferase M2-2 prevents the formation of neurotoxic aminochrome and dopachrome by catalyzing the conjugation of dopamine and dopa o-quinone with glutathione. NMR analysis of dopamine and dopa o-quinone-glutathione conjugates revealed that the addition of glutathione was at C-5 to form 5-S-glutathionyl-dopamine and 5-S-glutathionyl-dopa, respectively. Both conjugates were found to be resistant to oxidation by biological oxidizing agents such as O(2), H(2)O(2), and O(*-)(2), and the glutathione transferase-catalyzed reaction can therefore serve a neuroprotective antioxidant function.

Aminochrome was found to be toxic in a mouse-derived neuronal cell line (CNh). The effect was concentration dependent (10-150microM). The issue whether aminochrome toxicity involves glutamate transmission was studied with several glutamate receptors antagonists. Incubation of the cells with aminochrome (150microM) in the presence of 100microM of the AMPA antagonist, NBQX resulted in an increase of cell survival, from 52 to 73%. However, this protective effect did not seem to be related to activation of ionotropic glutamate receptors since incubation of CNh cells with 200microM of glutamate resulted in only 10% decrease of cell survival. However, NBQX was found to inhibit in vitro the autoxidation process. One hundred microM AP-5 did not have any effect on aminochrome toxicity. The toxic effect of aminochrome on CNh cells seems to be dependent of extracellular activation since addition of dicoumarol, a specific inhibitor of DT-diaphorase, did not affect that toxicity, which can be explained perhaps by a lack of a transport system for aminochrome into the CNh cells.

Angiotensin receptor II mRNA was found to be expressed in dopaminergic neuronal cell line RCSN3 of rat substantia nigra using RT-PCR reaction. Aminochrome (150 μM), a metabolite of the dopamine oxidative pathway, was found to down regulate the expression of angiotensin receptor mRNA in RCSN3 cells by 83% (p < 0.05).