Maternal behavior, novelty confrontation, and subcortical c-Fos expression during lactation period are shaped by gestational environment.

The environmental context during gestation may modulate the postpartum variations in maternal behaviors observed within different animal species. Most of our experimental knowledge on this phenomenon and its physiological effects have been gained by confronting the pregnant mother with stressful situations, with the consensual results indicating a reduced maternal behavior and a hyper reactivity of stress-related neural paths. Here, in contrast, by exposing nulliparous rats strictly during pregnancy to a standard laboratory environment (STD) or a highly stimulating sensory and social environment (EE), we investigated the hypothesis that subjects frequently exposed to social stimuli and novel situations during pregnancy will show postpartum changes in subcortical brain areas' activity related to the processing of social stimuli and novelty, such that there will be modifications in maternal behavior. We found that EE mothers doubled the levels of licking and grooming, and active hovering over pups during the first postpartum week than STD dams, without a difference in the time of contact with the pups. Associated with these behaviors, EE dams showed increased c-Fos immunoreaction in hypothalamic nuclei and distinct responses in amygdalar nuclei, than STD dams. In the maternal defensive test, EE dams tripled the levels of aggressive behaviors of the STD rats. Additionally, in two different tests, EE mothers showed lower levels of postpartum anxiety-like behaviors when confronted with novel situations. Our results demonstrate that the activity of brain areas related to social behavior is adaptable by environmental circumstances experienced during gestation, presumably to prepare the progeny for these particular conditions.

Daidzein Pro-cognitive Effects Coincided with Changes of Brain Neurotensin1 Receptor and Interleukin-10 Expression Levels in Obese Hamsters.

At present, concerns are pointing to "tasteful" high-fat diets as a cause of conditioning physical-social states that through alterations of some key emotional- and nutritional-related limbic circuits such as hypothalamic and amygdalar areas lead to obesity states. Feeding and energetic homeostatic molecular mechanisms are part of a complex neuronal circuit accounting for this metabolic disorder. In an attempt to exclude conventional drugs for treating obesity, daidzein, a natural glycosidic isoflavone, which mimics estrogenic neuroprotective properties against increased body weight, is beginning to be preferred. In this study, evident anxiolytic-like behaviors were detected following treatment of high-fat diet hamsters with daidzein as shown by extremely evident (p < 0.001) exploration tendencies in novel object recognition test and a notably greater amount of time spent (p < 0.01) in open arms of elevated plus maze. Moreover, the isoflavone promoted a protective role against neurodegeneration processes as shown by few, if any, amino cupric silver granules in amygdalar, hypothalamic and hippocampal neuronal fields when compared with obese hamsters. Interestingly, elevated expression levels of the anorexic neuropeptide receptor neurotensin1 in the above limbic areas of obese hamsters were extremely reduced by daidzein, especially during recovery of cognitive events. Contextually, such effects were strongly paralleled by increased levels of the anti-neuroinflammatory cytokine, interleukin-10. Our results corroborate a neuroprotective ability of this natural glycosidic isoflavone, which through its interaction with the receptor neurotensin1 and interleukin-10 pathways is correlated not only to improved feeding states, and subsequently obesity conditions, but above all to cognitive performances.

Sexually dimorphic patterns in electroencephalography power spectrum and autism-related behaviors in a rat model of fragile X syndrome.

Fragile X syndrome (FXS), a neurodevelopmental disorder with autistic features, is caused by the loss of the fragile X mental retardation protein. Sex-specific differences in the clinical profile have been observed in FXS patients, but few studies have directly compared males and females in rodent models of FXS. To address this, we performed electroencephalography (EEG) recordings and a battery of autism-related behavioral tasks on juvenile and young adult Fmr1 knockout (KO) rats. EEG analysis demonstrated that compared to wild-type, male Fmr1 KO rats showed an increase in gamma frequency band power in the frontal cortex during the sleep-like immobile state, and both male and female KO rats failed to show an increase in delta frequency power in the sleep-like state, as observed in wild-type rats. Previous studies of EEG profiles in FXS subjects also reported abnormally increased gamma frequency band power, highlighting this parameter as a potential translatable biomarker. Both male and female Fmr1 KO rats displayed reduced exploratory behaviors in the center zone of the open field test, and increased distance travelled in an analysis of 24-h home cage activity, an effect that was more prominent during the nocturnal phase. Reduced wins against wild-type opponents in the tube test of social dominance was seen in both sexes. In contrast, increased repetitive behaviors in the wood chew test was observed in male but not female KO rats, while increased freezing in a fear conditioning test was observed only in the female KO rats. Our findings highlight sex differences between male and female Fmr1 KO rats, and indicate that the rat model of FXS could be a useful tool for the development of new therapeutics for treating this debilitating neurodevelopmental disorder.

N,N-dimethylglycine prevents toluene-induced impairment in recognition memory and synaptic plasticity in mice.

Toluene intoxication produces deleterious effects on cognitive function, which has been associated with the inhibition of N-methyl-d-aspartate receptor (NMDAR). The present study determined whether N,N-dimethylglycine (DMG), a nutrient supplement and a partial agonist for NMDAR glycine binding site, could counteract recognition memory deficits and hippocampal synaptic dysfunction after acute toluene exposure. Male ICR mice were treated with toluene (250-750 mg/kg) for monitoring the sociability and social novelty in three-chamber test and long-term potentiation (LTP) of hippocampal synaptic transmission. Moreover, the combined effects of DMG (30-100 mg/kg) pretreatment with toluene (750 mg/kg) on three-chamber test, novel location and object recognition test and synaptic function were determined. Toluene decreased the sociability, preference for social novelty, hippocampal synaptic transmission and LTP in a dose-dependent manner. DMG pretreatment significantly reduced the toluene-induced memory impairment in social recognition, object location and object recognition and synaptic dysfunction. Furthermore, NMDAR glycine binding site antagonist, 7-chlorokynurenic acid, abolished the protective effects of DMG. These results indicate that DMG could prevent toluene-induced recognition memory deficits and synaptic dysfunction and its beneficial effects might be associated with modulation of NMDAR. These findings suggest that DMG supplementation might be an effective approach to prevent memory problems for the workers at risk of high-level toluene exposure or toluene abusers.

Perinatal Docosahexaenoic Acid Supplementation Improves Cognition and Alters Brain Functional Organization in Piglets.

Epidemiologic studies associate maternal docosahexaenoic acid (DHA)/DHA-containing seafood intake with enhanced cognitive development; although, it should be noted that interventional trials show inconsistent findings. We examined perinatal DHA supplementation on cognitive performance, brain anatomical and functional organization, and the brain monoamine neurotransmitter status of offspring using a piglet model. Sows were fed a control (CON) or a diet containing DHA (DHA) from late gestation throughout lactation. Piglets underwent an open field test (OFT), an object recognition test (ORT), and magnetic resonance imaging (MRI) to acquire anatomical, diffusion tensor imaging (DTI), and resting-state functional MRI (rs-fMRI) at weaning. Piglets from DHA-fed sows spent 95% more time sniffing the walls than CON in OFT and exhibited an elevated interest in the novel object in ORT, while CON piglets demonstrated no preference. Maternal DHA supplementation increased fiber length and tended to increase fractional anisotropy in the hippocampus of offspring than CON. DHA piglets exhibited increased functional connectivity in the cerebellar, visual, and default mode network and decreased activity in executive control and sensorimotor network compared to CON. The brain monoamine neurotransmitter levels did not differ in healthy offspring. Perinatal DHA supplementation may increase exploratory behaviors, improve recognition memory, enhance fiber tract integrity, and alter brain functional organization in offspring at weaning.

Psychoactive properties of BNN27, a novel neurosteroid derivate, in male and female rats.

RATIONALE: Νeurosteroids, like dehydroepiandrosterone (DHEA), play an important role in neurodegeneration and neural protection, but they are metabolized in androgens, estrogens, or other active metabolites. A newly developed synthetic DHEA analog, BNN27 ((20R)-3ß,21-dihydroxy-17R,20-epoxy-5-pregnene), exerts neurotrophic and neuroprotective actions without estrogenic or androgenic effects. OBJECTIVES: This study aimed to investigate potential anxiolytic or antidepressant properties of BNN27. METHODS: Male and female adult Wistar rats were treated with BNN27 (10, 30, or 90 mg/kg, i.p.) and subjected to behavioral tests measuring locomotion, exploration, and "depressive-like" behavior (open field, light/dark box, hole-board, and forced swim tests). The hippocampus and prefrontal cortex were collected for glutamate and GABA measurements, and trunk blood was collected for gonadal hormone analysis. RESULTS: Acute high-dose BNN27 reduced locomotion and exploratory behavior in both sexes. Intermediate acute doses (30 mg/kg) of BNN27 reduced exploration and testosterone levels only in males, and enhanced progesterone levels in both sexes. Notably, with the present design, BNN27 had neither anxiolytic nor antidepressant effects and did not affect estrogen levels. Interestingly, acute administration of a low BNN27 dose (10 mg/kg) increased glutamate turnover, GABA, and glutamine levels in the hippocampus. The same dose also enhanced glutamate levels in the prefrontal cortex of males only. Sex differences were apparent in the basal levels of behavioral, hormonal, and neurochemical parameters, as expected. CONCLUSIONS: BNN27 affects locomotion, progesterone, and testosterone levels, as well as the glutamatergic and GABAergic systems of the hippocampus and prefrontal cortex in a sex-dependent way.

Shared striatal activity in decisions to satisfy curiosity and hunger at the risk of electric shocks.

Curiosity is often portrayed as a desirable feature of human faculty. However, curiosity may come at a cost that sometimes puts people in harmful situations. Here, using a set of behavioural and neuroimaging experiments with stimuli that strongly trigger curiosity (for example, magic tricks), we examine the psychological and neural mechanisms underlying the motivational effect of curiosity. We consistently demonstrate that across different samples, people are indeed willing to gamble, subjecting themselves to electric shocks to satisfy their curiosity for trivial knowledge that carries no apparent instrumental value. Also, this influence of curiosity shares common neural mechanisms with that of hunger for food. In particular, we show that acceptance (compared to rejection) of curiosity-driven or incentive-driven gambles is accompanied by enhanced activity in the ventral striatum when curiosity or hunger was elicited, which extends into the dorsal striatum when participants made a decision.

Dietary Melatonin Protects Against Behavioural, Metabolic, Oxidative, and Organ Morphological Changes in Mice that are Fed High-Fat, High- Sugar Diet.

BACKGROUND: Metabolic syndrome is a complex pattern of disorders that occur jointly and is associated with an increased risk of cardiovascular and cerebrovascular disease. Therefore the need for more-efficient options of treatment has become imperative. OBJECTIVE: This study examined the effect of dietary-melatonin in the management of behavioural, metabolic, antioxidant, and organ changes due to high-fat/high-sugar (HFHS) diet-induced metabolic syndrome in mice. METHODS: Mice were randomly assigned into five groups of ten animals each. Groups were normal control [fed standard diet (SD)], HFHS control, and 3 groups of melatonin incorporated into HFHS at 2.5, 5, and 10 mg/kg of feed. Mice were fed for seven weeks, and body weight was assessed weekly. Open-field behaviours, radial-arm, and Y-maze spatial memory were scored at the end of the experimental period. Twenty-four hours after the last behavioural test, blood was taken for estimation of blood glucose levels after an overnight fast. Animals were then euthanised, and blood was taken for estimation of plasma insulin, leptin, and adiponectin levels, and serum lipid profile. The liver, kidneys, and brain were excised and processed for general histology, while homogenates of the liver and whole brain were used to assess oxidative stress parameters. RESULTS: Results showed that dietary melatonin (compared to HFHS diet) was associated with a decrease in body weight, food intake, and novelty-induced behaviours; and an increase in spatial-working memory scores. A decrease in glucose, insulin, leptin, and malondialdehyde levels; and an increase in adiponectin levels and superoxide dismutase activity were also observed. Histomorphological/ histomorphometric examination revealed evidence of organ injury with HFHS diet, and varying degrees of amelioration with melatonin-supplemented diet. CONCLUSION: In conclusion, dietary melatonin supplementation may have beneficial effects in the management of the metabolic syndrome.

Impact of magnetic fields generated by AC/DC submarine power cables on the behavior of juvenile European lobster (Homarus gammarus).

The number of submarine power cables using either direct or alternating current is expected to increase drastically in coming decades. Data concerning the impact of magnetic fields generated by these cables on marine invertebrates are scarce. In this context, the aim of this study was to explore the potential impact of anthropogenic static and time-varying magnetic fields on the behavior of recently settled juvenile European lobsters (Homarus gammarus) using two different behavioral assays. Day-light conditions were used to stimulate the sheltering behavior and facilitate the video tracking. We showed that juvenile lobsters did not exhibit any change of behavior when submitted to an artificial magnetic field gradient (maximum intensity of 200 µT) compared to non-exposed lobsters in the ambient magnetic field. Additionally, no influence was noted on either the lobsters' ability to find shelter or modified their exploratory behavior after one week of exposure to anthropogenic magnetic fields (225 ±â€¯5 µT) which remained similar to those observed in control individuals. It appears that static and time-varying anthropogenic magnetic fields, at these intensities, do not significantly impact the behavior of juvenile European lobsters in daylight conditions. Nevertheless, to form a complete picture for this biological model, further studies are needed on the other life stages as they may respond differently.

Reduced home cage and social activity in Pou3f2⊿ mice.

Pou3f2/Brn2 is a transcription factor that helps to determine the cellular identity of neocortical or hypothalamic neurons. Mammalian Pou3f2 contains three homopolymeric amino acids that are not present in amphibian Pou3f2. These amino acids contribute to monoamine function, which may play specific roles in mammalian development and behavior. Previous work has indicated that Pou3f2⊿ mice, which lack the homopolymeric amino acids, exhibited declined maternal activity and impaired object and spatial recognition. The current study, analyzed weight gain, brain development, home cage activity, social interaction, and response to novel objects in Pou3f2⊿ mice to determine which aspects of behavior were affected by monoamine dysregulation. Compared to their wild type counterparts, Pou3f2⊿ mice showed decreased social interaction and reduced home cage activity during their active phase. However, they showed normal weight gain, brain development, and responses to novelty. These results indicate that monoamine dysregulation in Pou3f2⊿ mice may specifically affect basal activity and social development, without altering non-social motivation.

Lard-rich and canola oil-rich high-fat diets during pregnancy promote rats' offspring neurodevelopmental delay and behavioral disorders.

High-fat diets (HFDs) during pregnancy may damage the neural development and emotional behavior of rat offspring. Therefore, we investigated the neurobehavioral development of rat offspring who were fed a control diet (CD) or an HFD with lard (HFD-lard) or canola oil (HFD-canola oil), during pregnancy. Offspring's neurodevelopment (somatic growth, physical maturation, and ontogenesis reflex) was assessed while they were suckling. The rat's levels of depression, anxiety, and aggression were assessed through forced swimming, elevation plus a maze or open field test, and a foot-shock test on postnatal days 60, 80, and 110, respectively. Maternal HFDs with lard or canola oil promoted rats' offspring during suckling. They had reduced body weight and growth, physical maturation delay (auditory conduit and eyes opening to both groups HFDs-lard and canola oil; ear unfolding and incisor eruption only HFD-lard) and an ontogenesis reflex (palm grasp/vibrissa placing to both groups HFDs-lard and canola oil, and free-fall righting only in HFD-lard). Negative geotaxis resulted in the faster development of the HFD-lard offspring. Furthermore, in adulthood, the HDFs-offspring were more likely to be overweight, have shorter swimming times in the swim test, greater susceptibility to anxiety with an increased time spent in the closed arm in the elevated plus-maze while spending less time in the open arm, and having a decreased number of crossings and rearing in the open field. On the other hand, aggressive-like behavior was not affected. Therefore, these findings indicate that maternal HFDs enriched with lard or canola oil during pregnancy can impair the neurodevelopment of rat offspring and can perhaps be associated with possible changes to the emotional behavior of adult offspring.

The Effects of Acute Neonatal Pain on Expression of Corticotropin-Releasing Hormone and Juvenile Anxiety in a Rodent Model.

Premature infants in the neonatal intensive care unit (NICU) may be subjected to numerous painful procedures without analgesics. One necessary, though acutely painful, procedure is the use of heel lances to monitor blood composition. The current study examined the acute effects of neonatal pain on maternal behavior as well as amygdalar and hypothalamic activation, and the long-term effects of neonatal pain on later-life anxiety-like behavior, using a rodent model. Neonatal manipulations consisted of either painful needle pricks or non-painful tactile stimulation in subjects' left plantar paw surface which occurred four times daily during the first week of life [postnatal day (PND)1-PND7]. Additionally, maternal behaviors in manipulated litters were compared against undisturbed litters via scoring of videotaped interactions to examine the long-term effects of pain on dam-pup interactions. Select subjects underwent neonatal brain collection (PND6) and fluorescent in situ hybridization (FISH) for corticotropin-releasing hormone (CRH) and the immediate early gene c-fos. Other subjects were raised to juvenile age (PND24 and PND25) and underwent innate anxiety testing utilizing an elevated plus maze (EPM) protocol. FISH indicated that neonatal pain influenced amygdalar CRH and c-fos expression, predominately in males. No significant increase in c-fos or CRH expression was observed in the hypothalamus. Additionally, neonatal pain altered anxiety behaviors independent of sex, with neonatal pain subjects showing the highest frequency of exploratory behavior. Neonatal manipulations did not alter maternal behaviors. Overall, neonatal pain drives CRH expression and produces behavioral changes in anxiety that persist until the juvenile stage.

Dynamic Network Activation of Hypothalamic MCH Neurons in REM Sleep and Exploratory Behavior.

Most brain neurons are active in waking, but hypothalamic neurons that synthesize the neuropeptide melanin-concentrating hormone (MCH) are claimed to be active only during sleep, particularly rapid eye movement (REM) sleep. Here we use deep-brain imaging to identify changes in fluorescence of the genetically encoded calcium (Ca2+) indicator GCaMP6 in individual hypothalamic neurons that contain MCH. An in vitro electrophysiology study determined a strong relationship between depolarization and Ca2+ fluorescence in MCH neurons. In 10 freely behaving MCH-cre mice (male and female), the highest fluorescence occurred in all recorded neurons (n = 106) in REM sleep relative to quiet waking or non-REM sleep. Unexpectedly, 70% of the MCH neurons had strong fluorescence activity when the mice explored novel objects. Spatial and temporal mapping of the change in fluorescence between pairs of MCH neurons revealed dynamic activation of MCH neurons during REM sleep and activation of a subset of the same neurons during exploratory behavior. Functional network activity maps will facilitate comparisons of not only single-neuron activity, but also network responses in different conditions and disease.SIGNIFICANCE STATEMENT Functional activity maps identify brain circuits responding to specific behaviors, including rapid eye movement sleep (REM sleep), a sleep phase when the brain is as active as in waking. To provide the first activity map of individual neurons during REM sleep, we use deep-brain calcium imaging in unrestrained mice to map the activity of hypothalamic melanin-concentrating hormone (MCH) neurons. MCH neurons were found to be synchronously active during REM sleep, and also during the exploration of novel objects. Spatial mapping revealed dynamic network activation during REM sleep and activation of a subset of the neurons during exploratory behavior. Functional activity maps at the cellular level in specific behaviors, including sleep, are needed to establish a brain connectome.

Bacopa monnieri Supplements Offset Paraquat-Induced Behavioral Phenotype and Brain Oxidative Pathways in Mice.

BACKGROUND: Parkinson's Disease (PD) is characterized by alterations in cerebellum and basal ganglia functioning with corresponding motor deficits and neuropsychiatric symptoms. Involvement of oxidative dysfunction has been implicated for the progression of PD, and environmental neurotoxin exposure could influence such behavior and psychiatric pathology. Assessing dietary supplementation strategies with naturally occurring phytochemicals to reduce behavioral anomalies associated with neurotoxin exposure would have major clinical importance. The present investigation assessed the influence of Bacopa monneri (BM) on behaviors considered to reflect anxiety-like state and motor function as well as selected biochemical changes in brain regions of mice chronically exposed to ecologically relevant herbicide, paraquat (PQ). MATERIALS & METHODS: Male mice (4-week old, Swiss) were daily provided with oral supplements of standardized BM extract (200 mg/kg body weight/day; 3 weeks) and PQ (10 mg/kg, i.p. three times a week; 3 weeks). RESULTS: We found that BM supplementation significantly reversed the PQ-induced reduction of exploratory behavior, gait abnormalities (stride length and mismatch of paw placement) and motor impairment (rotarod performance). In a separate study, BM administration prevented the reduction in dopamine levels and reversed cholinergic activity in brain regions important for motor (striatum) pathology. Further, in mitochondria, PQ-induced decrease in succinate dehydrogenase (SDH) activity and energy charge (MTT reduction), was restored with BM supplementation. CONCLUSION: These findings suggest that BM supplementation mitigates paraquat-induced behavioral deficits and brain oxidative stress in mice. However, further investigations would enable us to identify specific molecular mechanism by which BM influences behavioural pathology.

Carvacrol ameliorates behavioral disturbances and DNA damage in the brain of rats exposed to propiconazole.

Propiconazole (PCZ) is an ergosterol biosynthesis inhibiting fungicide. Carvacrol (CAR) is a monoterpenoid phenol that has various beneficial health effects. The current research was designed to study the impact of PCZ on the behavior of rats and its ability to induce DNA damage in neurons as well as to clarify the ameliorative effect of CAR against these toxic impacts. Sixty Sprague-Dawley rats were randomly and equally divided into 4 experimental groups and treated daily by oral gavage for 2 months as follows: Group 1 (control); group 2 treated with PCZ (75 mg/kg); group 3 treated with CAR (50 mg/kg) and group 4 treated with both PCZ and CAR. Behavioral tests demonstrated that exposure to PCZ had a deleterious effect on psychological, motor and cognitive neural functions. Additionally, antioxidant enzyme activities, SOD and GSH-Px, were declined in brain tissue following exposure to PCZ. Moreover, comet assay revealed a high percent of DNA damage in the brain of rats exposed to PCZ. On the other hand, CAR administration ameliorated the harmful effects induced by PCZ through a protective mechanism that involved the improvement of neural functions and attenuation of oxidative stress and DNA damage.

Shank3B mutant mice display pitch discrimination enhancements and learning deficits.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by a core set of atypical behaviors in social-communicative and repetitive-motor domains. Individual profiles are widely heterogeneous and include language skills ranging from nonverbal to hyperlexic. The causal mechanisms underlying ASD remain poorly understood but appear to include a complex combination of polygenic and environmental risk factors. SHANK3 (SH3 and multiple ankyrin repeat domains 3) is one of a subset of well-replicated ASD-risk genes (i.e., genes demonstrating ASD associations in multiple studies), with haploinsufficiency of SHANK3 following deletion or de novo mutation seen in about 1% of non-syndromic ASD. SHANK3 is a synaptic scaffolding protein enriched in the postsynaptic density of excitatory synapses. In order to more closely evaluate the contribution of SHANK3 to neurodevelopmental expression of ASD, a knockout mouse model with a mutation in the PDZ domain was developed. Initial research showed compulsive/repetitive behaviors and impaired social interactions in these mice, replicating two core ASD features. The current study was designed to further examine Shank3B heterozygous and homozygous knockout mice for behaviors that might map onto atypical language in ASD (e.g., auditory processing, and learning/memory). We report findings of repetitive and atypical aggressive social behaviors (replicating prior reports), novel evidence that Shank3B KO mice have atypical auditory processing (low-level enhancements that might have a direct relationship with heightened pitch discrimination seen in ASD), as well as robust learning impairments.

Immediate and persistent antidepressant-like effects of Chaihu-jia-Longgu-Muli-tang are associated with instantly up-regulated BDNF in the hippocampus of mice.

Conventional antidepressants have a disadvantage in delayed onset of efficacy. Here, we aimed to evaluate the immediate and persistent antidepressant-like action of a classic herbal medicine Chaihu-jia-Longgu-Muli decoction (CLM) as well as the action of CLM on hippocampal brain-derived neurotrophic factor (BDNF) over time. CLM consists of Xiaochaihu decoction (XchD), Longgu-Muli (LM) and several other herbs. The contribution of constituent herbal formula XchD and other parts of CLM was also assessed. Following a single dose of CLM, tail suspension test (TST), forced swim test (FST), and novelty-suppressed feeding test (NSF) were performed. The antidepressant activity of XchD, its interaction with LM or remaining parts of CLM was also examined after a single administration. BDNF expression in the hippocampus was examined at 30 min and 24 hr post a single CLM. A single administration of half of clinical dose of CLM elicited antidepressant effects at TST 30 min post administration, and lasted for 72 hr. Furthermore, CLM also reduced the latency to eat in NSF test. A single proportional dose of XchD induced antidepressant effects at 30 min and lasted for 48 hr, whereas the effect lasted for 72 hr when combined with either LM or the remaining parts of CLM. BDNF expression increased at 30 min and persisted at least for 24 hr after a single dose of CLM. The results support that Chaihu-jia-Longgu-Muli decoction was capable to immediately and enduringly elicit antidepressant activity via enhancement of hippocampal BDNF expression, in which the constituent Xiaochaihu decoction played the primary role.

Aberrant Somatosensory Processing and Connectivity in Mice Lacking Engrailed-2.

Overreactivity and defensive behaviors in response to tactile stimuli are common symptoms in autism spectrum disorder (ASD) patients. Similarly, somatosensory hypersensitivity has also been described in mice lacking ASD-associated genes such as Fmr1 (fragile X mental retardation protein 1). Fmr1 knock-out mice also show reduced functional connectivity between sensory cortical areas, which may represent an endogenous biomarker for their hypersensitivity. Here, we measured whole-brain functional connectivity in Engrailed-2 knock-out (En2-/-) adult mice, which show a lower expression of Fmr1 and anatomical defects common to Fmr1 knock-outs. MRI-based resting-state functional connectivity in adult En2-/- mice revealed significantly reduced synchronization in somatosensory-auditory/associative cortices and dorsal thalamus, suggesting the presence of aberrant somatosensory processing in these mutants. Accordingly, when tested in the whisker nuisance test, En2-/- but not WT mice of both sexes showed fear behavior in response to repeated whisker stimulation. En2-/- mice undergoing this test exhibited decreased c-Fos-positive neurons (a marker of neuronal activity) in layer IV of the primary somatosensory cortex and increased immunoreactive cells in the basolateral amygdala compared with WT littermates. Conversely, when tested in a sensory maze, En2-/- and WT mice spent a comparable time in whisker-guided exploration, indicating that whisker-mediated behaviors are otherwise preserved in En2 mutants. Therefore, fearful responses to somatosensory stimuli in En2-/- mice are accompanied by reduced basal connectivity of sensory regions, reduced activation of somatosensory cortex, and increased activation of the basolateral amygdala, suggesting that impaired somatosensory processing is a common feature in mice lacking ASD-related genes.SIGNIFICANCE STATEMENT Overreactivity to tactile stimuli is a common symptom in autism spectrum disorder (ASD) patients. Recent studies performed in mice bearing ASD-related mutations confirmed these findings. Here, we evaluated the behavioral response to whisker stimulation in mice lacking the ASD-related gene Engrailed-2 (En2-/- mice). Compared with WT controls, En2-/- mice showed reduced functional connectivity in the somatosensory cortex, which was paralleled by fear behavior, reduced activation of somatosensory cortex, and increased activation of the basolateral amygdala in response to repeated whisker stimulation. These results suggest that impaired somatosensory signal processing is a common feature in mice harboring ASD-related mutations.

Effects of stress on behavior and resting-state fMRI in rats and evaluation of Telmisartan therapy in a stress-induced depression model.

BACKGROUND: The etiology of depression and its effective therapeutic treatment have not been clearly identified. Using behavioral phenotyping and resting-state functional magnetic resonance imaging (r-fMRI), we investigated the behavioral impact and cerebral alterations of chronic unpredictable mild stress (CUMS) in the rat. We also evaluated the efficacy of telmisartan therapy in this rodent model of depression. METHODS: Thirty-two rats were divided into 4 groups: a control group(C group), a stress group(S group), a stress + telmisartan(0.5 mg/kg)group (T-0.5 mg/kg group) and a stress + telmisartan(1 mg/kg) group (T-1 mg/kg group). A behavioral battery, including an open field test (OFT), a sucrose preference test (SPT), and an object recognition test (ORT), as well as r-fMRI were conducted after 4 weeks of CUMS and telmisartan therapy. The r-fMRI data were analyzed using the amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) approach. The group differences in the behavior and r-fMRI test results as well as the correlations between these 2 approaches were examined. RESULTS: CUMS reduced the number of rearings and the total moved distance in OFT, the sucrose preference in SPT, and novel object recognition ability in ORT. The telmisartan treatment (1 mg/kg) significantly improved B-A/B + A in the ORT and improved latency scores in the OFT and SPT. The S group exhibited a decreased ReHo in the motor cortex and pons, but increased ReHo in the thalamus, visual cortex, midbrain, cerebellum, hippocampus, hypothalamus, and olfactory cortex compared to the C group. Telmisartan (1 mg/kg)reversed or attenuated the stress-induced changes in the motor cortex, midbrain, thalamus, hippocampus, hypothalamus, visual cortex, and olfactory cortex. A negative correlation was found between OFT rearing and ReHo values in the thalamus. Two positive correlations were found between ORT B-A and the ReHo values in the olfactory cortexand pons. CONCLUSIONS: Telmisartan may be an effective complementary drug for individuals with depression who also exhibit memory impairments. Stress induced widespread regional alterations in the cerebrum in ReHo measures while telmissartan can reverse part of theses alterations. These data lend support for future research on the pathology of depression and provide a new insight into the effects of telmisartan on brain function in depression.

Blast-induced brain injury in rats leads to transient vestibulomotor deficits and persistent orofacial pain.

Blast-induced traumatic brain injury (blast-TBI) is associated with vestibulomotor dysfunction, persistent post-traumatic headaches and post-traumatic stress disorder, requiring extensive treatments and reducing quality-of-life. Treatment and prevention of these devastating outcomes require an understanding of their underlying pathophysiology through studies that take advantage of animal models. Here, we report that cranium-directed blast-TBI in rats results in signs of pain that last at least 8 weeks after injury. These occur without significantly elevated behavioural markers of anxiety-like conditions and are not associated with glial up-regulation in sensory thalamic nuclei. These injuries also produce transient vestibulomotor abnormalities that resolve within 3 weeks of injury. Thus, blast-TBI in rats recapitulates aspects of the human condition.