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Bale Laboratory

Our research focuses on developing mouse models of stress sensitivity related to neurodevelopmental and neuropsychiatric disease. We utilize genetic and prenatal manipulations to elucidate mechanisms contributing to disease predisposition.

We have focused on utilizing approaches that range from fetal antecedents in programming of long-term disease risk to genetic targeting of cell type specific knockout mice.

We have focused on developing models of disease including affective disorders and obesity utilizing approaches that range from fetal antecedents, involved in programming of long-term disease risk, to genetic targeting of cell type specific knockouts.

We have initiated multiple lines of investigation that will provide insight into the timing and sex specificity of early life events promoting disease susceptibility, the maturation of central pathways during key periods of development, and the epigenetic mechanisms involved in long-term effects following stress exposure.

 

Research Interests

Developing mouse models of stress sensitivity using genetic and prenatal manipulations to to understand the mechanism and heritability for increased susceptibility to neurodevelopmental disorders. Determine the molecular mechanisms by which stress factors influence appetite and reward. Examine the effects of maternal stress-sensitivity on fetal development and long-term physiological and behavioral responses.

Research Techniques

Genetic mouse models for behavioral analyses including stress, anxiety, depression, feeding and reward models; gene expression and epigenetic identification by in situ hybridization, real-time PCR, PCR Arrays, ChIP, bisulfite sequencing; biochemistry using Western blot; molecular biology for gene detection; and plasma hormone detection using radioimmune assays.

Projects

CRF & 5HT & Mood

  • Stress pathway dysregulation is the most pervasive symptom in neuropsychiatric disease. Patients with schizophrenia and autism show heightened stress sensitivity and exacerbated symptoms during stress experience.
  • It has long been postulated that a hyperactive stress system links stress dysregulation to neuropsychiatric disease, which has promoted the pharmaceutical pursuit of therapeutic targets including antagonists of the CRF receptor-1 (CRFR1) that would blunt this response.
  • Utilizing CRF receptor-2 (CRFR2) deficient mice in which disruption of normal stress neurocircuitry prevents the recruitment and promotion of homeostatic mechanisms during stress, we have demonstrated that an inability to adapt to stress has severe consequences, including cell death within the 5-HT producing raphe nucleus, maladaptive physiological and behavioral stress responses, and increased perseverative behaviors.
  • CRFR2-deficient mice showed elevated proinflammatory cytokines and their downstream effectors including proapoptotic caspases, increased markers of microglia infiltration, and a 20-fold increased level of the CRF binding protein (CRF-BP).
  • These alterations likely contribute to the increased cell death and stress-sensitivity phenotype in these mice.
  • Therefore, we hypothesize that cytokine-induced increases in CRF-BP prevent CRF from activating postsynaptic CRFR1, producing a counterintuitive hypoactive response in the raphe and an inhibition of the normal stress-induced 5-HTergic neurotransmission necessary to promote arousal and coping behaviors.

Early Pregnancy Stress Programming of Offspring Emotionality

  • Sex-biased neurodevelopmental disorders, including schizophrenia, have been associated with maternal stress experienced during pregnancy.
  • We have recently identified a specific period of early pregnancy where male offspring were sensitive to the effects of maternal stress, displaying as adults behaviors and stress physiology suggestive of brain feminization.
  • Our hypothesis to be examined in these proposed studies is that prenatal stress exerts programming effects on the developing male brain via changes in methylation patterns affecting testis development and testosterone production during the organizational period of sexually dimorphic brain development. Organizational and activational testosterone has been shown to be important in programming of male stress neurocircuitry.
  • Stress pathway dysregulation and sensitivity is a hallmark of most neuropsychiatric disorders. Therefore, these studies are designed:
  1. To determine the contribution of SRY gene methylation and expression in the programming of a feminized stress-sensitive phenotype of early prenatal stress male mice.
  2. To examine the heritability of early prenatal stress effects in second generation offspring to identify possible gene targets of PNS that may be epigenetically modified in the germline.
  3. To utilize prenatal testosterone treatment or DNMT1 inhibition to ameliorate the effects of early prenatal stress on male offspring stress sensitivity.
  • Determination of the fetal antecedents and mechanisms by which alterations in brain development of these circuits occur, and identification of potential heritable aspects of this phenotype may provide insight into novel therapeutic targets and disease prevention.

Early Gestation as a Sensitive Period to Stress in Sex-Dependent Neurodevelopment

  • The mechanism through which fetal antecedents contribute to disease development is not understood, though likely involves a complex interaction between maternal environment, placental changes, embryo sex and epigenetic programming. As most neurodevelopmental disorders exhibit a sex bias in presentation, elucidation of the mechanisms by which sex-specific susceptibility arises is likely to provide critical insight into disease etiology.
  • We have recently identified a sensitive period of early gestation where stress has sex-specific long- term programming effects on offspring stress pathway neurodevelopment.
  • Mechanistically, we have detected sex-specific effects of maternal stress on placental inflammatory cytokines, growth factors and epigenetic machinery. From these studies, we hypothesize that early pregnancy is a highly sensitive period for the long- term sex-specific consequences of maternal stress through effects on placental inflammation, epigenetic machinery and nutrient transport altering programming of the developing embryo.
  • Therefore, our studies will examine:
  1. How early prenatal stress (EPS) alters the long-term programming of stress pathway neurodevelopment through sex-specific placental and embryonic inflammation, nutrient transport and changes in epigenetic machinery during a highly sensitive period of early gestation
  2. The possible rescue of the sex- specific programming effects of EPS by maternal treatment with an anti-inflammatory or a specific inhibitor of NFkB activation, NBD
  3. Genomic and proteomic technology including ChIP-Sequencing and pathway focused PCR Arrays to analyze placental and embryonic brain tissues and proteomic analysis of amniotic fluid across gestation to identify potential translatable biomarkers and genes important in the programming of stress dysregulation predictive of neurodevelopmental disorders in EPS offspring.

 

(For a full, up to date list of publications, please go to: Dr. Bale's Pubmed Link.)

2013

 Rodgers AB, Morgan CP, Bronson SL, Revello S, Bale TL. 2013. Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation. J Neurosci 33(21):9003-12

Halpern CH, Tekriwal A, Santollo J, Keating JG, Wolf JA, Daniels D, Bale TL. 2013 Amelioration of binge eating by nucleus accumbans shell deep brain stimulation in mice involves d2 receptor modulation.  J Neurosci 33(17):7122-9

Howerton, CL, Morgan CP, Fischer DB, Bale TL. 2013. O-GlcNAc transferase (OGT) as a placental bioarker of maternal stress and reprogramming of CNS gene transcription in development. Proc Natl Acad Sci 110(13):5169-74

2012

Morgan CP, and Bale TL 2012. Sex differences in microRNA regulation of gene expression: no smoke, just miRs. 3(1):22

Epperson, CN & Bale, TL 2012. BDNF Val66 Met Polymorphism and Brain-Derived Neurotrophic Factor Levels Across the Female Life Span: Implications for the Sex Bias in Affective Disorders. Biol Psychiatry. 15;72(6):434-6

Gerber, AR & Bale, TL 2012. Antiinflammatory treatment ameliorates HPA stress axis dysfunction in a mouse model of stress sensitivity. Endocrinology. 153(10)4830-7.

Bale, TL & Chen, A 2012. Minireview: CRF and Wylie Vale: A Story of 41 Amino Acids and a Texan with Grit. Endocrinology, 153(6):2556-61.

Howerton, CL & Bale, TL 2012. Prenatal programing: At the intersection of maternal stress and immune activation. Horm Behav. 62(3):237-42

2011

Morgan, CP & Bale, TL 2011. Early prenatal stress epigenetically programs dysmasculinization in second-generation offspring via the paternal lineage. J Neurosci, 31, 11748-11755.

Goel, N, Plyler, KS, Daniels, D & Bale, TL 2011. Androgenic influence on serotonergic activation of the HPA stress axis. Endocrinology, 152, 2001-2010.

Dunn, GA, Morgan, CP & Bale, TL. 2011. Sex-specificity in transgenerational epigenetic programming. Horm Behav, 59, 290-295.

Dunn, GA & Bale, TL. 2011. Maternal high-fat diet effects on third-generation female body size via the paternal lineage. Endocrinology, 152, 2228-2236.

Bale, TL 2011. Sex differences in prenatal epigenetic programming of stress pathways. Stress-the International Journal on the Biology of Stress, 14, 348-356.

Bale, TL. 2011. Stressing the importance of development. Interview by Kristie Nybo. Biotechniques, 51, 369.

2011

Pankevich DE, Teegarden SL, Hedin AD, Jensen CL, Bale TL. 2010. Caloric restriction experience reprograms stress and orexigenic pathways and promotes binge eating. J Neurosci. 2010 Dec 1;30(48):16399-407.

Bale TL, Baram TZ, Brown AS, Goldstein JM, Insel TR, McCarthy MM, Nemeroff CB, Reyes TM, Simerly RB, Susser ES, Nestler EJ. Early life programming and neurodevelopmental disorders. 2010. Biol Psychiatry. 2010 Aug 15;68(4):314-9.

Goel N, Bale TL. Sex differences in the serotonergic influence on the hypothalamic-pituitary-adrenal stress axis. 2010 Endocrinology. Apr;151(4):1784-94. Epub 2010 Feb 25.

Principal Investigator

Tracy Bale, BS, PhD

  • Professor of Neuroscience, Department of Animal Biology, School of Veterinary Medicine University of Pennsylvania
  • Professor of Neuroscience, Department of Psychiatry , University of Pennsylvania
  • Director, Neuroscience Center, School of Veterinary Medicine

 Post-Doctoral Fellows

Stefanie Bronson, Ph.D.
Ph.D. (Neuroscience) U. of Cincinnati ’11
B.S. (Music / Psychology) Stetson U. ’02
Joined Bale Lab in 2011
sbronson@vet.upenn.edu

Casey Halpern, MD
MD Perelman School of Medicine ’07
B.A. (Chemistry / Classics) University of Pennsylvania ’03
Joined Bale Lab in 2010
Casey.Halpern@uphs.upenn.edu

Christopher Howerton, Ph.D.
Ph.D. (Animal Behavior) UC Davis ’11
M.A. (Animal Science) UC Davis
B.A. (Animal Biology) UC Davis
Joined Bale Lab in 2011
chowerto@vet.upenn.edu

Katie Morrison, Ph. D.
Ph.D. (Biological Psychology) U. Tennessee ’12
B.S. (Biology/Psychology) West Virginia U. ’06
Joined Bale Lab in 2012
kmorr@vet.upenn.edu

Graduate Students

Alexis Gerber
B.A. (Biology/Neurobiology) Macalester Coll ’07
Neuroscience Graduate Group
Joined Bale Lab in 2010
agerb@mail.med.upenn.edu

Christopher Morgan
B.A. (Biology) St Mary’s College ’06
Pharmacology Graduate Group
Joined Bale Lab in 2009
morganch@mail.med.upenn.edu

Ali Rodgers
B.S. (Biology) Notre Dame ’09
Neuroscience Graduate Group
Joined Bale Lab in 2011
abuch@mail.med.upenn.edu
 
Laboratory Technicians & Research Assistants

Jessica Fluharty
B.S. (Health Sciences) U. of Hartford ’09
Joined Bale Lab in 2010
jflu@vet.upenn.edu

Anand Tekriwal
B.S. (Biological Basis of Behavior)
University of Pennsylvania ’13
Joined Bale Lab in 2011
tekriwal@sas.upenn.edu