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      Gestational and early postnatal hypothyroidism alters VGluT1 and VGAT bouton distribution in the neocortex and hippocampus, and behavior in rats

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          Abstract

          Thyroid hormones are fundamental for the expression of genes involved in the development of the CNS and their deficiency is associated with a wide spectrum of neurological diseases including mental retardation, attention deficit-hyperactivity disorder and autism spectrum disorders. We examined in rat whether developmental and early postnatal hypothyroidism affects the distribution of vesicular glutamate transporter-1 (VGluT1; glutamatergic) and vesicular inhibitory amino acid transporter (VGAT; GABAergic) immunoreactive (ir) boutons in the hippocampus and somatosensory cortex, and the behavior of the pups. Hypothyroidism was induced by adding 0.02% methimazole (MMI) and 1% KClO 4 to the drinking water starting at embryonic day 10 (E10; developmental hypothyroidism) and E21 (early postnatal hypothyroidism) until day of sacrifice at postnatal day 50. Behavior was studied using the acoustic prepulse inhibition (somatosensory attention) and the elevated plus-maze (anxiety-like assessment) tests. The distribution, density and size of VGluT1-ir and VGAT-ir boutons in the hippocampus and somatosensory cortex was abnormal in MMI pups and these changes correlate with behavioral changes, as prepulse inhibition of the startle response amplitude was reduced, and the percentage of time spent in open arms increased. In conclusion, both developmental and early postnatal hypothyroidism significantly decreases the ratio of GABAergic to glutamatergic boutons in dentate gyrus leading to an abnormal flow of information to the hippocampus and infragranular layers of the somatosensory cortex, and alter behavior in rats. Our data show cytoarchitectonic alterations in the basic excitatory hippocampal loop, and in local inhibitory circuits of the somatosensory cortex and hippocampus that might contribute to the delayed neurocognitive outcome observed in thyroid hormone deficient children born in iodine deficient areas, or suffering from congenital hypothyroidism.

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          How inhibition shapes cortical activity.

          Cortical processing reflects the interplay of synaptic excitation and synaptic inhibition. Rapidly accumulating evidence is highlighting the crucial role of inhibition in shaping spontaneous and sensory-evoked cortical activity and thus underscores how a better knowledge of inhibitory circuits is necessary for our understanding of cortical function. We discuss current views of how inhibition regulates the function of cortical neurons and point to a number of important open questions. Copyright © 2011 Elsevier Inc. All rights reserved.
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            The many faces of CREB.

            The transcription factor CREB is best known for its involvement in learning and memory. However, emerging evidence suggests that CREB activity has very different roles--sometimes beneficial, sometimes detrimental--depending on the brain region involved. Induction of CREB in the hippocampus by antidepressant treatments could contribute to their therapeutic efficacy. By contrast, activation of CREB in the nucleus accumbens and several other regions by drugs of abuse or stress mediates certain aspects of drug addiction, and depressive and anxiety-like behaviors. These complexities suggest that strategies that exploit regional differences in upstream factors or that target specific CREB-regulated genes, rather than CREB itself, could make a promising contribution to the treatment of neuropsychiatric conditions.
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              Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies.

              Since the mid-1970s, cross-species translational studies of prepulse inhibition (PPI) have increased at an astounding pace as the value of this neurobiologically informative measure has been optimized. PPI occurs when a relatively weak sensory event (the prepulse) is presented 30-500 ms before a strong startle-inducing stimulus, and reduces the magnitude of the startle response. In humans, PPI occurs in a robust, predictable manner when the prepulse and startling stimuli occur in either the same or different modalities (acoustic, visual, or cutaneous). This review covers three areas of interest in human PPI studies. First, we review the normal influences on PPI related to the underlying construct of sensori- (prepulse) motor (startle reflex) gating. Second, we review PPI studies in psychopathological disorders that form a family of gating disorders. Third, we review the relatively limited but interesting and rapidly expanding literature on pharmacological influences on PPI in humans. All studies identified by a computerized literature search that addressed the three topics of this review were compiled and evaluated. The principal studies were summarized in appropriate tables. The major influences on PPI as a measure of sensorimotor gating can be grouped into 11 domains. Most of these domains are similar across species, supporting the value of PPI studies in translational comparisons across species. The most prominent literature describing deficits in PPI in psychiatrically defined groups features schizophrenia-spectrum patients and their clinically unaffected relatives. These findings support the use of PPI as an endophenotype in genetic studies. Additional groups of psychopathologically disordered patients with neuropathology involving cortico-striato-pallido-pontine circuits exhibit poor gating of motor, sensory, or cognitive information and corresponding PPI deficits. These groups include patients with obsessive compulsive disorder, Tourette's syndrome, blepharospasm, temporal lobe epilepsy with psychosis, enuresis, and perhaps posttraumatic stress disorder (PTSD). Several pharmacological manipulations have been examined for their effects on PPI in healthy human subjects. In some cases, the alterations in PPI produced by these drugs in animals correspond to similar effects in humans. Specifically, dopamine agonists disrupt and nicotine increases PPI in at least some human studies. With some other compounds, however, the effects seen in humans appear to differ from those reported in animals. For example, the PPI-increasing effects of the glutamate antagonist ketamine and the serotonin releaser MDMA in humans are opposite to the PPI-disruptive effects of these compounds in rodents. Considerable evidence supports a high degree of homology between measures of PPI in rodents and humans, consistent with the use of PPI as a cross-species measure of sensorimotor gating. Multiple investigations of PPI using a variety of methods and parameters confirm that deficits in PPI are evident in schizophrenia-spectrum patients and in certain other disorders in which gating mechanisms are disturbed. In contrast to the extensive literature on clinical populations, much more work is required to clarify the degree of correspondence between pharmacological effects on PPI in healthy humans and those reported in animals.
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                Author and article information

                Contributors
                Journal
                Front Neuroanat
                Front Neuroanat
                Front. Neuroanat.
                Frontiers in Neuroanatomy
                Frontiers Media S.A.
                1662-5129
                17 February 2015
                2015
                : 9
                Affiliations
                1Departamento de Histología y Anatomía, Facultad de Medicina, Universidad Miguel Hernández Alicante, Spain
                2Instituto de Neuroetología, Universidad Veracruzana Xalapa, Veracruz, México
                3Instituto de Neurociencias de Alicante, Universidad Miguel Hernández and Consejo Superior de Investigaciones Científicas Alicante, Spain
                4Instituto de investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid Madrid, Spain
                Author notes

                Edited by: Javier DeFelipe, Cajal Institute, Spain

                Reviewed by: Fiorenzo Conti, Universita Politecnica delle Marche, Italy; Irmgard Dorothea Dietzel-Meyer, Ruhr University, Germany

                *Correspondence: Pere Berbel, Departamento de Histología y Anatomía, Universidad Miguel Hernández, Av. Ramón y Cajal s/n, Sant Joan d'Alacant, 03550 Alicante, Spain e-mail: pere.berbel@ 123456umh.es

                This article was submitted to the journal Frontiers in Neuroanatomy.

                Article
                10.3389/fnana.2015.00009
                4330898
                Copyright © 2015 Navarro, Alvarado, Navarrete, Giner, Obregon, Manzanares and Berbel.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 15, Tables: 0, Equations: 0, References: 189, Pages: 24, Words: 17134
                Categories
                Neuroscience
                Original Research Article

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