Brain derived neurotrophic factor (BDNF) is importantly involved in anxiety, depression and cognitive function. A single nucleotide polymorphism, a valine (Val) to methionine (Met) substitution (Val66Met) in the BDNF gene, results in increased mood and cognitive disorders in both humans and mice. Depression rates rise sharply in women during perimenopause, which is the 7-10 year period before menopause characterized by declining estrogen levels and gradual acyclicity. Evidence from humans and mice that have undergone surgical menopause indicate that estrogen plays a critical role ameliorating anxiety and memory dysfunctions and in modulating the expression of BDNF and its receptor TrkB in the hippocampus, a region critically involved in anxiety and memory. Determining whether disruption of estrogen cyclicity during perimenopause contributes to the greater susceptibility of carriers of Val66Met allele to depression and anxiety disorders and BDNF signaling in the hippocampus has been hampered due to a lack of a rodent model. However, the recent development of a novel model that induces menopause through gradual ovarian cessation now allows for the replication of the perimenopausal period in heterozygote Val66Met mice. Therefore, this proposal will test the central hypothesis that a single copy of Val66Met allele intensifies the mood and memory disorders seen during perimenopause and leads to disruption of BDNF signaling mediated by estrogen in the hippocampus. A multidisciplinary approach combining behavioral measures including open field, object placement and object recognition and quantitative in situ hybridization and light and electron microscopic immunocytochemical methods for the localization of BDNF and TrkB will test this hypothesis.
Aim 1 will determine if, after surgical menopause induced by ovariectomy, Val/Met mice experience even greater anxiety and memory problems and less BDNF signaling that Val/Val (control) mice and if these effects can be reversed by estrogen replacement.
Aim 2 will determine if during perimenopause disruption of estrogen cyclicity leads to reduced BDNF signaling and increased behavioral instability in anxiety and cognitive tests that are worse in Val/Met than Val/Val mice. Understanding the impact of BDNF genotype and altered estrogen status on mood and cognitive disorders could ultimately lead to clinical treatments that are individualized for sex, genotype and life stage.
In a subpopulation of women, the incidences of anxiety, depression and cognitive dysfunction increase during the transition to menopause (i.e., perimenopause). The proposed studies will use novel rodent models to determine if, during perimenopause, a mutation in the neurotropin brain derived neurotrophic factor (BDNF) gene exacerbates anxiety and cognitive problems and concomitantly alters BDNF communication in the brain. These studies will provide information on the interaction of estrogen and BDNF in affective disorders and could lead to improved hormone replacement therapies to alleviate menopausal symptoms.
|Van Kempen, Tracey A; Narayan, Ankita; Waters, Elizabeth M et al. (2016) Alterations in the subcellular distribution of NADPH oxidase p47(phox) in hypothalamic paraventricular neurons following slow-pressor angiotensin II hypertension in female mice with accelerated ovarian failure. J Comp Neurol 524:2251-65|
|Mazid, Sanoara; Hall, Baila S; Odell, Shannon C et al. (2016) Sex differences in subcellular distribution of delta opioid receptors in the rat hippocampus in response to acute and chronic stress. Neurobiol Stress 5:37-53|
|Marques-Lopes, Jose; Lynch, Mary-Katherine; Van Kempen, Tracey A et al. (2015) Female protection from slow-pressor effects of angiotensin II involves prevention of ROS production independent of NMDA receptor trafficking in hypothalamic neurons expressing angiotensin 1A receptors. Synapse 69:148-65|
|Waters, Elizabeth M; Thompson, Louisa I; Patel, Parth et al. (2015) G-protein-coupled estrogen receptor 1 is anatomically positioned to modulate synaptic plasticity in the mouse hippocampus. J Neurosci 35:2384-97|
|Van Kempen, Tracey A; Gorecka, Jolanta; Gonzalez, Andreina D et al. (2014) Characterization of neural estrogen signaling and neurotrophic changes in the accelerated ovarian failure mouse model of menopause. Endocrinology 155:3610-23|
|Pierce, Joseph P; Kelter, David T; McEwen, Bruce S et al. (2014) Hippocampal mossy fiber leu-enkephalin immunoreactivity in female rats is significantly altered following both acute and chronic stress. J Chem Neuroanat 55:9-17|
|Marques-Lopes, Jose; Van Kempen, Tracey; Waters, Elizabeth M et al. (2014) Slow-pressor angiotensin II hypertension and concomitant dendritic NMDA receptor trafficking in estrogen receptor ?-containing neurons of the mouse hypothalamic paraventricular nucleus are sex and age dependent. J Comp Neurol 522:3075-90|
|Milner, Teresa A; Burstein, Suzanne R; Marrone, Gina F et al. (2013) Stress differentially alters mu opioid receptor density and trafficking in parvalbumin-containing interneurons in the female and male rat hippocampus. Synapse 67:757-72|
|Gray, J D; Milner, T A; McEwen, B S (2013) Dynamic plasticity: the role of glucocorticoids, brain-derived neurotrophic factor and other trophic factors. Neuroscience 239:214-27|
|Burstein, Suzanne R; Williams, Tanya J; Lane, Diane A et al. (2013) The influences of reproductive status and acute stress on the levels of phosphorylated delta opioid receptor immunoreactivity in rat hippocampus. Brain Res 1518:71-81|
Showing the most recent 10 out of 14 publications