title: Neural mechanisms underlying stress resilience in Ahi1 knockout mice: relevance to neuropsychiatric disorders.
abstract: The Abelson helper integration site 1 (AHI1) gene has a pivotal role in brain development. Studies by our group and others have demonstrated association of AHI1 with schizophrenia and autism. To elucidate the mechanism whereby alteration in AHI1 expression may be implicated in the pathogenesis of neuropsychiatric disorders, we studied Ahi1 heterozygous knockout (Ahi1(+/-)) mice. Although their performance was not different from wild-type mice on tests that model classical schizophrenia-related endophenotypes, Ahi1(+/-) mice displayed an anxiolytic-like phenotype across different converging modalities. Using behavioral paradigms that involve exposure to environmental and social stress, significantly decreased anxiety was evident in the open field, elevated plus maze and dark-light box, as well as during social interaction in pairs. Assessment of core temperature and corticosterone secretion revealed a significantly blunted response of the autonomic nervous system and the hypothalamic-pituitary-adrenal axis in Ahi1(+/-) mice exposed to environmental and visceral stress. However, response to centrally acting anxiogenic compounds was intact. On resting-state functional MRI, connectivity of the amygdala with other brain regions involved in processing of anxiogenic stimuli and inhibitory avoidance learning, such as the lateral entorhinal cortex, ventral hippocampus and ventral tegmental area, was significantly reduced in the mutant mice. Taken together, our data link Ahi1 under-expression with a defect in the process of threat detection. Alternatively, the results could be interpreted as representing an anxiety-related endophenotype, possibly granting the Ahi1(+/-) mouse relative resilience to various types of stress. The current knockout model highlights the contribution of translational approaches to understanding the genetic basis of emotional regulation and its associated neurocircuitry, with possible relevance to neuropsychiatric disorders.
authors.affiliation: Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Lotan
authors.affiliation: Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: T
authors.initials: T
authors.lastname: Lifschytz
authors.affiliation: Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Slonimsky
authors.affiliation: Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: E C
authors.initials: EC
authors.lastname: Broner
authors.affiliation: Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: L
authors.initials: L
authors.lastname: Greenbaum
authors.affiliation: Cardiovascular Research Center, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Abedat
authors.affiliation: Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Fellig
authors.affiliation: Anxiety and Stress Research Unit, Ben-Gurion University of the Negev, Beersheba, Israel.
authors.forename: H
authors.initials: H
authors.lastname: Cohen
authors.affiliation: MRI Lab, Medical Biophysics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Lory
authors.affiliation: MRI Lab, Medical Biophysics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: G
authors.initials: G
authors.lastname: Goelman
authors.affiliation: Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: B
authors.initials: B
authors.lastname: Lerer
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000209:etiology / Q000503:physiopathology*; D001831:Body Temperature; D001921:Brain / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D003345:Corticosterone / Q000378:metabolism; D004777:Environment; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012146:Rest / Q000502:physiology; D012559:Schizophrenia / Q000503:physiopathology; D055139:Sensory Gating / Q000502:physiology; D012919:Social Behavior; D013315:Stress, Psychological / Q000150:complications / Q000503:physiopathology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C465818:Ahi1 protein, mouse; D011518:Proto-Oncogene Proteins; D003345:Corticosterone
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