Prenatal exposure of mice to an environmental estrogen alters sex differences in brain and behavior

56. PRENATAL EXPOSURE OF MICE TO A LOW-DOSE ENVIRONMENTAL ESTROGEN ALTERS SEX DIFFERENCES IN BRAIN AND BEHAVIOR. Palanza; P:; Ponzi, D., Gioiosa, L., Flugge, G., Parmigiani, S., and Fuchs, E. Dipartimento di Biologia Evolutiva, Universita` di Parma. Laboratory of Neurobiology, German Primate Center, Goettingen. The presence in the environment to a large number of environmental and industrial compounds that have estrogenic activity (Environmental Estrogens, EE) raises major health concerns. Sexually dimorphic behaviors are particularly useful to study the effects of low concentrations of EE, similar to environmental contamination, because they are highly sensitive to alterations of the endocrine mileu. Behavior is the endpoint of complex, integrated systems and therefore is a good biomarker of neuroendocrine and neurobiological alterations. We investigated the effects of prenatal exposure (via maternal treatment) to an environmental-like, low dose of bisphenol A (BPA, an estrogenic compound used in food industry) on mice behavioral response to novelty and on the noradrenergic system in the brain. Mice were tested in a free-choice novelty preference test at adolescence, in a freeexploratory open field and elevated plus-maze (EPM) as adults. Both adolescent and adult mice exposed to BPAshowed either a decrease or a reversion in sexual differences in response to novelty. Contrary to the control profile, BPA-exposed males and females did not differ in exploration, an effect due mainly to changes in BPA-exposed females relative to controls. As adults, mice were sacrificed and their brain were analyzed for alpha2 adrenergic receptor system in locus coeruleus (LC) and preoptic area (PO). Control mice showed a sexually dimorphic profile of receptor density in the PO, while prenatal BPA-exposure lowered such sex differences; BPA-exposed males showed increased receptors number, thus resulting more similar to the control females’ profile. In both the PO and LC of exposed animals, a decreased affinity of alpha2-adrenergic receptors was observed

Behavioural, neural and cardiovascular adaptations in mice lacking the NPY Y1 receptor

Neuropeptide Y (NPY) is primarily synthesised and released by neurones, it is co-localised with noradrenaline and is involved in the regulation of cardiovascular function. In a mouse model lacking NPY Y1 receptor (KO), the ability of NPY to potentiate noradrenaline-induced vasoconstriction is abolished during stress but normal in baseline conditions, locomotor activity and metabolic rate are lowered, blood insulin levels and glucose storage activity are increased. The present study was aimed at further characterising NPY Y1 mutants, with special emphasis on: behavioural responses to novelty seeking and open-field with objects tests, heart rate responsiveness during acute social defeat, alpha2-adrenoceptor (alpha2-ARs) function in brain areas involved in cardiovascular regulation, and cardiac structure. As compared to wild-type controls (n=9), NPY Y1 KOs (n=9) showed: reduced somatomotor activation during non-social challenges, lower heart rate in baseline conditions, larger heart rate responsiveness during social defeat, increased number of alpha2-ARs in the dorsal motor nucleus of the vagus (nX) and the locus coeruleus (LC), moderately larger volume fraction of myocardial fibrosis. The remarkable increment of alpha2-adrenoceptor density in the nX and LC allows to view KO mice behavioural and anatomo-physiological peripheral characteristics as 'adaptations' to central adrenergic rearrangement due to NPY Y1 receptor deletion

The stress-regulated protein M6a is a key modulator for neurite outgrowth and filopodium/spine formation

Neuronal remodeling is a fundamental process by which the brain responds to environmental influences, e.g., during stress. In the hippocampus, chronic stress causes retraction of dendrites in CA3 pyramidal neurons. We have recently identified the glycoprotein M6a as a stress-responsive gene in the hippocampal formation. This gene is down-regulated in the hippocampus of both socially and physically stressed animals, and this effect can be reversed by antidepressant treatment. In the present work, we analyzed the biological function of the M6a protein. Immunohistochemistry showed that the M6a protein is abundant in all hippocampal subregions, and subcellular analysis in primary hippocampal neurons revealed its presence in membrane protrusions (filopodia/spines). Transfection experiments revealed that M6a overexpression induces neurite formation and increases filopodia density in hippocampal neurons. M6a knockdown with small interference RNA methodology showed that M6a low-expressing neurons display decreased filopodia number and a lower density of synaptophysin clusters. Taken together, our findings indicate that M6a plays an important role in neurite/filopodium outgrowth and synapse formation. Therefore, reduced M6a expression might be responsible for the morphological alterations found in the hippocampus of chronically stressed animals. Potential mechanisms that might explain the biological effects of M6a are discussed