Igor Branchi

Polybrominated Diphenyl Ethers: Neurobehavioral Effects Following Developmental Exposure

Polybrominated diphenyl ethers (PBDEs), a class of widely used flame retardants, are becoming widespread environmental pollutants, as indicated by studies on sentinel animal species, as well as humans. Of particular concern are the reported increasingly high levels of PBDEs in human milk, as should be given that almost no information is available on their potential effects on developing organisms. In order to address this issue, studies have been conducted in mice and rats to assess the potential neurotoxic effects of perinatal exposure to PBDEs (congeners 47, 99, 153 and the penta-BDE mixture DE-71). Characteristic endpoints of PBDE neurotoxicity are, among others, endocrine disruption (e.g. decreased thyroid hormone levels), alteration in cholinergic system activity (behavioral hyporesponsivity to nicotine challenge), as well as alterations of several behavioral parameters. In particular, the main hallmark of PBDE neurotoxicity is a marked hyperactivity at adulthood. Furthermore, a deficit in learning and memory processes has been found at adulthood in neonatally exposed animals. Some of neurotoxic effects of PBDEs are comparable to those of polychlorinated biphenyls (PCBs), though the latter class of compounds seems to exert a stronger toxic effect. Available information on PBDE neurotoxicity obtained from animal studies and the possibility of neonatal exposure to PBDEs via the mothers milk suggest that these compounds may represent a potential risk for neurobehavioral development in humans.

Early Social Enrichment Shapes Social Behavior and Nerve Growth Factor and Brain-Derived Neurotrophic Factor Levels in the Adult Mouse Brain

BACKGROUND Early experiences produce persistent changes in brain and behavioral function. We investigate whether being reared in a communal nest (CN), a form of early social enrichment that characterizes the natural ecological niche of many rodent species including the mouse, has effects on adult social/aggressive behavior and nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) levels in mice. METHODS The CN consisted of a single nest where three mothers kept their pups together and shared care-giving behavior from birth to weaning (postnatal day 25). RESULTS Compared to standard laboratory conditions, in CN condition, mouse mothers displayed higher levels of maternal care. At adulthood, CN mice displayed higher propensity to interact socially and achieved more promptly the behavioral profile of either dominant or subordinate male. Furthermore, CN adult mice showed higher NGF levels, which were further affected by social status, and higher BDNF levels in the brain. CONCLUSIONS Our findings indicate that CN, a highly stimulating early social environment, produces differences in social behavior later in life associated with marked changes of neurotrophin levels in selected brain areas, including hippocampus and hypothalamus.

The mouse communal nest: investigating the epigenetic influences of the early social environment on brain and behavior development.

Among the epigenetic factors shaping brain and behavior during early postnatal life, social experiences have a major impact. Early social experiences are mainly of two kinds: mother-offspring and peer interaction. In rodents, the latter has so far been rarely studied. The communal nest (CN) is an innovative experimental strategy that favors an exhaustive investigation of the long-term effects not only of mother-offspring but also of peer interaction. CN is a rearing condition employed by up to 90% of mouse females in naturalistic settings and consists of a single nest where two or more mothers keep their pups together and share care-giving. Mice reared in a communal nest display relevant changes in brain function and behavior, including high levels of neural plasticity markers, such as brain-derived neurotrophic factor (BDNF), and elaborate adult social competencies. Overall, CN appears as an experimental strategy different and complementary to the ones currently used for studying how the early environment determines developmental trajectories.

Hypertension Induces Brain β-Amyloid Accumulation, Cognitive Impairment, and Memory Deterioration Through Activation of Receptor for Advanced Glycation End Products in Brain Vasculature

Although epidemiological data associate hypertension with a strong predisposition to develop Alzheimer disease, no mechanistic explanation exists so far. We developed a model of hypertension, obtained by transverse aortic constriction, leading to alterations typical of Alzheimer disease, such as amyloid plaques, neuroinflammation, blood-brain barrier dysfunction, and cognitive impairment, shown here for the first time. The aim of this work was to investigate the mechanisms involved in Alzheimer disease of hypertensive mice. We focused on receptor for advanced glycation end products (RAGE) that critically regulates A&bgr; transport at the blood-brain barrier and could be influenced by vascular factors. The hypertensive challenge had an early and sustained effect on RAGE upregulation in brain vessels of the cortex and hippocampus. Interestingly, RAGE inhibition protected from hypertension-induced Alzheimer pathology, as showed by rescue from cognitive impairment and parenchymal A&bgr; deposition. The increased RAGE expression in transverse aortic coarctation mice was induced by increased circulating advanced glycation end products and sustained by their later deposition in brain vessels. Interestingly, a daily treatment with an advanced glycation end product inhibitor or antioxidant prevented the development of Alzheimer traits. So far, Alzheimer pathology in experimental animal models has been recognized using only transgenic mice overexpressing amyloid precursor. This is the first study demonstrating that a chronic vascular insult can activate brain vascular RAGE, favoring parenchymal A&bgr; deposition and the onset of cognitive deterioration. Overall we demonstrate that RAGE activation in brain vessels is a crucial pathogenetic event in hypertension-induced Alzheimer disease, suggesting that inhibiting this target can limit the onset of vascular-related Alzheimer disease.

Ultrasonic vocalizations by infant laboratory mice: A preliminary spectrographic characterization under different conditions

During the first 2 to 3 weeks of life, isolated neonatal mice emit ultrasonic vocalizations, with various conditions such as hypothermia or olfactory or tactile stimulation eliciting this behavior. Although it is known that pup vocalizations stimulate prompt expression of maternal behavior, the communicative role of infant ultrasonic calls is still a matter of investigation. A fine-grained spectrographic analysis of ultrasonic calls emitted by pups exposed to different conditions was performed. Forty 8-day-old outbred CD-1 mice (Mus musculus) were isolated from their mothers and littermates and randomly exposed to one of the following conditions: (a) odor from the nest, (b) social isolation, (c) low temperature-isolation, (d) tactile stimulation, or (e) odor from a conspecific adult male. Upon consideration of the spectrogram typology and emission frequency interval, it appears that the conditions under which vocalizations are emitted influence the sound characteristics of call production.

Early social enrichment augments adult hippocampal BDNF levels and survival of BrdU-positive cells while increasing anxiety- and “depression”-like behavior

Early experiences affect brain function and behavior at adulthood. Being reared in a communal nest (CN), consisting of a single nest where three mothers keep their pups together and share care‐giving behavior from birth to weaning (postnatal day [PND] 25), provides an highly socially stimulating environment to the developing pup. Communal nest characterizes the natural ecologic niche of many rodent species including the mouse. At adulthood, CN reared mice, compared to mice reared in standard nesting laboratory condition (SN), show an increase in BDNF protein levels and longer survival of BrdU‐positive cells in the hippocampus. Open field and elevated plus maze results indicate that CN mice, although showing levels of exploratory and locomotor activity similar to those of SN mice, displayed increased anxiety‐like behavior, performing more thigmotaxis in the open field and spending less time in the open arms of the plus maze. Furthermore, CN mice displayed higher levels of immobility behavior in the forced swim test. Overall, these findings show that CN, an highly stimulating early social environment, increases adult neuronal plasticity, as suggested by high BDNF levels and augmented number of newly generated cells in the hippocampus, which is associated to an increased anxiety‐ and “depression”‐like behavior. These findings are discussed in the framework of the neurotrophin hypothesis of depression.

Long-term effects of the periadolescent environment on exploratory activity and aggressive behaviour in mice: social versus physical enrichment

The aims of the present study were (i) to investigate the effects of environmental enrichment during periadolescence on different behavioural and neurochemical responses in male CD-1 mice at adulthood and (ii) to describe the relative role of the physical and social components of the enrichment in producing these effects. Thirty 5-day-old mice were randomly assigned to one of the following housing conditions lasting five consecutive days: (i) individually housed in a standard cage, (ii) housed in pairs in a standard cage, (iii) individually housed in a physically enriched cage, and (iv) housed in pairs in a physically enriched cage. At adulthood, 80 days after the enrichment exposure, the explorative behaviour in an open field, as well as the behaviour in agonistic encounters, was evaluated in association with the analysis of selected central (hypothalamic levels of nerve growth factor (NGF) and brain-derived growth factor(BDNF)) and peripheral (plasma corticosterone levels) biochemical parameters. The results show that the long-term effects of the physical and the social enrichment are different and not additive. In particular, while social enrichment by itself exerted very limited effects, physical enrichment decreased the exploratory activity and altered social behaviour. Mice housed in pairs in an enriched cage showed low activity levels in the open field, and they tended to become more frequently dominant, although showing a more affiliative and less aggressive social interaction strategy. Furthermore, they presented low levels of hypothalamic NGF and high levels of brain-derived growth factor, suggesting an important effect of the combination of social and physical enrichment on neurobehavioral markers of brain plasticity and on animal ability to cope with social challenges.

Early life influences on emotional reactivity: evidence that social enrichment has greater effects than handling on anxiety-like behaviors, neuroendocrine responses to stress and central BDNF levels

During the early post-natal phases the brain is experience-seeking and provided by a considerable plasticity which allows a fine tuning between the external environment and the developing organism. Since the early work of Seymour Levine, an impressive amount of research has clearly shown that stressful experiences exert powerful effects on the brain and body development. These effects can last throughout the entire life span influencing brain function and increasing the risk for depression and anxiety disorders. The mechanisms underlying the effects of early stress on the developing organism have been widely studied in rodents through experimental manipulations of the post-natal environment, such as handling, which have been shown to exert important effects on the emotional phenotype and the response to stress. In the present paper we review the relevant literature and present some original data indicating that, compared to handling, which imposes an external manipulation on the mother-infant relationship, social enrichment, in the form of communal rearing, in mice has very profound effects on animals emotionality and the response to stress. These effects are also accompanied by important changes in central levels of brain-derived neurotrophic factor. The present data indicate that communal rearing has more pervasive effects than handling, strengthening previous data suggesting that it is a good animal model of reduced susceptibility to depression-like behavior. Overall, the availability of ever more sophisticated animal models represents a fundamental tool to translate basic research data into appropriate interventions for humans raised under traumatic or impoverished situations.

Nonmotor symptoms in Parkinson's disease: Investigating early-phase onset of behavioral dysfunction in the 6-hydroxydopamine-lesioned rat model

To investigate the psychiatric symptoms accompanying the early phases of Parkinsons disease (PD), we injected adult rats with 10.5 μg 6‐hydroxydopamine (6‐OHDA) bilaterally into the dorsal striatum. The resulting neurodegeneration led, 12 weeks after injection, to a mild (36%) reduction of striatal dopamine. We tested the behavioral response of sham and 6‐OHDA‐lesioned animals at different time points after injection to evaluate the onset and progression of behavioral abnormalities. The results showed that such a mild reduction of dopamine levels was associated with a decrease in anxiety‐like behavior, an increase in “depression”‐like behavior, and a marked change in social behavior. Learning and memory abilities were not affected. Overall, the PD rat model used here displays behavioral alterations having face validity with psychiatric symptoms of the pathology and thus appears to be a valuable tool for investigating the neural bases of the early phases of PD.

CX3CR1 Deficiency Alters Hippocampal-Dependent Plasticity Phenomena Blunting the Effects of Enriched Environment

In recent years several evidence demonstrated that some features of hippocampal biology, like neurogenesis, synaptic transmission, learning, and memory performances are deeply modulated by social, motor, and sensorial experiences. Fractalkine/CX3CL1 is a transmembrane chemokine abundantly expressed in the brain by neurons, where it modulates glutamatergic transmission and long-term plasticity processes regulating the intercellular communication between glia and neurons, being its specific receptor CX3CR1 expressed by microglia. In this paper we investigated the role of CX3CL1/CX3CR1 signaling on experience-dependent hippocampal plasticity processes. At this aim wt and CX3CR1GFP/GFP mice were exposed to long-lasting-enriched environment (EE) and the effects on hippocampal functions were studied by electrophysiological recordings of long-term potentiation of synaptic activity, behavioral tests of learning and memory in the Morris water maze paradigm and analysis of neurogenesis in the subgranular zone of the dentate gyrus (DG). We found that CX3CR1 deficiency increases hippocampal plasticity and spatial memory, blunting the potentiating effects of EE. In contrast, exposure to EE increased the number and migration of neural progenitors in the DG of both wt and CX3CR1GFP/GFP mice. These data indicate that CX3CL1/CX3CR1-mediated signaling is crucial for a normal experience-dependent modulation of hippocampal functions.