In this section
Joanna Dabrowska, PhD, PharmD
Cellular and Molecular Pharmacology Discipline
Center for Neurobiology of Stress Resilience and Psychiatric Disorders
Dr. Joanna Dabrowska earned a PharmD degree in 2000 from Wroclaw Medical University, School of Pharmacy, and a PhD in Neuropharmacology in 2006 from the Medical University of Silesia in Poland. She continued her postdoctoral training at Emory University in Atlanta and in 2014, she joined the faculty of the Chicago Medical School as an Assistant Professor of cellular and molecular pharmacology and neuroscience. She is now an Associate Professor of cellular and molecular pharmacology and faculty member of the Center for Neurobiology of Stress Resilience and Psychiatric Disorders. Joanna’s research has been continuously supported by the National Institute of Mental Health, NIH (K99/R00 MH096746, R01 MH113007, 2R01 MH113007) since 2014.
Research
Research Overview
Our lab has a long-standing interest in the neurobiology of stress-related psychiatric disorders including post-traumatic stress disorder (PTSD) and generalized anxiety disorder (GAD). The hallmarks of PTSD in humans include hyperarousal, inability to properly discriminate between stimuli that predict danger vs. stimuli that predict safety, and higher fear reactivity to unpredictable vs. predictable threats. To better understand the neurobiology of adaptive vs. maladaptive fear processing, we use rodent models of defensive behaviors, such as fear- and anxiety-potentiated startle (FPS and APS, respectively) in male and female rats. The interaction of many brain regions contributes to processing of fear memories. Our lab investigates the functional neuroanatomy of the extended amygdala, which comprises the bed nucleus of the stria terminalis (BNST) and the central amygdala (CeA), and their respective contributions to processing of unpredictable vs. predictable threats. Within this neurocircuitry, we are particularly interested in the neuromodulation by peptides (oxytocin, OT; vasopressin, AVP; corticotropin-releasing factor, CRF), their impact on specific neuronal populations and their unique roles in the regulation of the extended amygdala activity and fear behaviors. We utilize in vitro slice electrophysiology combined with optogenetics, neuronal tract tracing and immunofluorescence techniques, chemogenetics in transgenic rat models (OT-receptor-Cre, CRF-Cre, AVP-Cre), and behavioral testing (FPS, APS) to understand the cellular mechanisms of these neuropeptides’ actions in the extended amygdala. This research has a unique translational validity to anxiety disorders since human brain imaging has shown increased BNST activity in the conditions of uncertainty and hypervigilant threat monitoring and BNST hyperactivity in individuals with PTSD and GAD.
Current research projects:
1. The role of BNST→CeA neurons in processing predictable vs. unpredictable threats
In parallel with the BNST hyperactivity shown in PTSD patients, human imaging studies demonstrate an enhanced functional connectivity between the BNST and the centromedial amygdala in anxious individuals (PMID: 29107120; 29235190). Recent studies in rats also showed that dorsolateral BNST (BNSTDL) sends inhibitory projection to the CeA (PMID: 26400259) and this BNST→CeA output might facilitate anxiety-like behavior (PMID: 30240530). Since the BNST and CeA are highly interconnected via inhibitory and peptidergic projections, the dynamic interactions between the BNST-mediated generalized fear and the CeA-mediated cued fear, might determine an ultimate behavioral output in response to a threat. In this project, we use pathway-specific chemogenetics in combination with pharmacological approaches, fear- and anxiety-potentiated startle to establish the role of the BNST→CeA neurons in processing fear to predictable vs. unpredictable threats.
2. The role of oxytocin receptors (OTR) in the BNST in the modulation of fear and anxiety
The overall goal of the project is to determine if OTR neurotransmission in the BNST modulates fear and anxiety-like behavior and whether OT regulates activity of BNST neurons.
Determine the role of OT in the BNST in the regulation of anxiety and fear. Using intra-BNST infusions of selective OTR antagonist in male rats, we showed that OTR transmission in the BNST facilitates acquisition (but not consolidation) of cued fear, measured in the FPS (Dabrowska and Moaddab, 2017; Martinon et al., 2019; Janeček and Dabrowska, 2019). As this suggests that endogenous OT in the BNST is recruited during cued fear encoding, we performed in vivo microdialysis in freely-moving rats to measure OT content in BNST microdialysates before, during, and after cued or contextual fear conditioning. We demonstrated that cued (exposure to signaled foot shocks), but not contextual (un-signaled foot shocks) fear conditioning evokes OT release in the BNST (Martinon et al., 2019). We also showed that OT release in the BNST is modulated by CRF receptor type 2 (Martinon and Dabrowska, 2018). Finally, we demonstrate that cued and contextual fear conditioning differently recruit hypothalamic OT neurons (Martinon et al., 2019). These findings highlight the unique role of OTR transmission in the BNST in biasing fear learning toward imminent and predictable threats, (see review articles from the lab: Janeček and Dabrowska, 2019; Olivera-Pasilio and Dabrowska, 2020; Marvar et al., 2021).
Determine the role of OT in regulating activity of BNST neurons. The rat BNSTDL contains GABA-ergic neurons classified based on intrinsic membrane properties and firing pattern into three types, Type I-III. Using in vitro whole-cell patch-clamp recordings in male rats, we demonstrated that OT has cell-type specific effects in the BNST: 1) OT directly excites Type I neurons in an OTR-dependent fashion, as revealed by a depolarization of the resting membrane potential, increased input resistance, reduced rheobase, reduced fast and medium spike afterhyperpolarization, as well as a left shift in the spike frequency/current relationship. Using cell-attached mode, we show that the majority of Type I neurons fire spontaneously and that OT further potentiates this effect. 2) As a consequence, OT indirectly inhibits Type II BNST neurons. We show that OT increases the frequency, but not amplitude, of spontaneous inhibitory post-synaptic currents (sIPSCs) selectively in Type II neurons, an effect abolished by OTR antagonist or tetrodotoxin (TTX), and reduces spontaneous firing rate of Type II neurons. As the majority of Type II neurons project to the CeA (PMID: 30240530) we show that OT increases sIPSCs frequency in retrogradely labeled Type II CeA-projecting BNST (BNST→CeA) neurons (Francesconi et al., 2021).
Overall, these findings present a model of fine-tuned modulation by OT, which selectively excites Type I interneurons and inhibits Type II BNST→CeA output neurons via an indirect mechanism. By inhibiting the GABA-ergic BNST→CeA neurons, and disinhibiting the CeA, OTR activation in the BNST facilitates cued fear.
The role of OTR-neurons in the BNST in the regulation of BNST activity and fear behaviors
We use OTR-Cre transgenic rats (Cre-recombinase under OTR promoter, originally provided by Dr. Valery Grinevich, University of Heidelberg) and slice electrophysiology to investigate cellular phenotype and functional connectivity of OTR-neurons in the BNST. We use chemogenetics combined with behavioral testing such as FPS and elevated plus maze to investigate the role of OTR-neurons in the BNST in fear processing.
3. The role of vasopressin in modulating BNST activity and defensive behaviors
BNST neurons are innervated by OT and AVP fibers, but the cellular effects of AVP in the BNST are unknown. In this project we use behavioral and electrophysiological experiments to 1) Determine the integrated role of V1aR and OTR in modulating activity of BNST neurons, 2) Determine whether predictable vs. unpredictable threats differentially modulate activity of BNST→CeA neurons via OTR and V1aR, 3) Determine the role of BNST→CeA neurons in mediating fear responses to predictable vs. unpredictable threats, and the contribution of OTR vs. V1aR. By refining mechanisms underlying neuromodulation of BNST→CeA neurons, we will have a better understanding on how an imbalance in processing of predictable vs. unpredictable threats can lead to a hypervigilance and precipitate the onset of anxiety disorders.
4. Sex and strain differences in fear-potentiated startle
Although human FPS studies often use both sexes, surprisingly limited number of rodent FPS studies used females. In this project we investigate the effects of signal-threat contingency, signal-threat order and threat predictability on the FPS in both sexes. Specifically, we use classic FPS protocol and compare it to modified FPS (70% contingency or backward conditioning or cue and shock unpaired) and we investigate potential sex differences in these FPS protocols. Although males and females show similar FPS when conditioned with classic fear-conditioning, prominent sex difference is uncovered following fear-conditioning to unpredictable threats (cue and shock un-paired), with Wistar female rats showing significantly higher startle overall during the FPS recall, regardless of trial type as well as significantly higher contextual fear expression than males. This striking sex difference in processing unpredictable threats in rodent FPS might help to understand the mechanisms underlying higher incidence of PTSD in women.
Personnel
Dr. Fulvia Berton, PhD, Research Specialist
I work in the electrophysiological laboratory using rat brain slice preparation. I use the combination of patch clamp electrophysiological recordings with neuronal tract tracing and/or optogenetic stimulation in wild-type and transgenic rats to identify the role of Oxytocin (OT) or Vasopressin (AVP) on neuronal activity in the bed nucleus of the stria terminalis (BNST).
Rachel Chudoba, BSc, PhD Candidate
I study the role of neurons producing corticotropin-releasing factor (CRF) in the BNST in variety of defensive behaviors in males and female rats using chemogenetics in CRF-Cre transgenic rats (Cre-recombinase under CRF promoter, originally developed by Dr. Bob Messing, UT Austin). I’m complementing this work with in vitro electrophysiology recordings to understand the intrinsic membrane properties, synaptic activity, and intrinsic connectivity of CRF neurons in the BNST in male and female rats.
Dr. Walter Francesconi, PhD, Senior Research Associate
I am an electrophysiologist with an expertise and extensive experience in recording neuronal activity of the BNST, a brain region involved in addiction, fear, and anxiety-behaviors. Using a whole-cell patch clamp recordings from different types of electrophysiologically defined BNST neurons (Type I-III), in combination with optogenetic tools to evoke peptide release, I investigate the functional intrinsic organization of this neural hub and the neuromodulatory role of hypothalamic oxytocin and vasopressin peptidergic inputs on the BNST activity.
Lorena Monroy, Lake Forest College student, 2023-24 Bartram Research Scholar
I study the role of AVP neurons in the suprachiasmatic nucleus of the hypothalamus (SCN) in the regulation of defensive behaviors such as fear- and anxiety-related behaviors in male and female rats. I use chemogenetic techniques in AVP-Cre rats (Cre-recombinase under AVP promoter, originally created by Dr. Valery Grinevich, University of Heidelberg, Germany) to determine how the AVP-SCN neurons contribute to changing levels of defensive behaviors along the circadian rhythms.
Dr. Valentina Olivera-Pasilio, PhD, Postdoctoral Fellow
My project focuses on the role of oxytocin receptors and oxytocin receptors-expressing neurons in the BNST in the modulation of fear and anxiety-like responses. I use chemogenetics in OTR-Cre transgenic rats (Cre-recombinase under OTR promoter, originally created by Dr. Valery Grinevich, University of Heidelberg, Germany) to understand the role of OTR-neurons in the BNST in modulating these behaviors. I am also interested in studying the role of the projection neurons from the BNST to the central amygdala (CeA) in fear and anxiety, and how oxytocin receptors modulate activity of these projection neurons. Lastly, my work investigates sex and strain differences in fear-potentiated startle responses.
Susan H. Olson, BSc, Lab Manager
I work with lab personnel to ensure smooth and efficient lab operations. I make sure all safety protocols are followed at the bench and in animal care, I train individuals in the use and care of animals in research as well as various surgical techniques in order to help them progress in their research projects. I also specialize in the hypothalamic stereotaxic surgeries and help with implementation of circadian rhythms into the research projects.
Publications
Olivera-Pasilio V, Dabrowska J. Fear-Conditioning to Unpredictable Threats Reveals Sex and Strain Differences in Rat Fear-Potentiated Startle (FPS). Neuroscience. (2023) 530:108-132.
Dabrowska J. From recent advances in underlying neurocircuitry of fear and anxiety to promising pharmacotherapies for PTSD: The saga of heart, sex and the developing brain. Neuropharmacology. (2023) 232:109529.
Chudoba R, Dabrowska J. Distinct populations of corticotropin-releasing factor (CRF) neurons mediate divergent yet complementary defensive behaviors in response to a threat. J. Neuropharmacology. (2023) 228:109461.
Dabrowska J. Should I Freeze or Should I Go? The Ventral Subiculum → Bed Nucleus of the Stria Terminalis Neurons Yield the Right-of-way. Neuroscience. (2022) 502:117-118.
Beyeler A, Dabrowska J. Neuronal diversity of the amygdala and the bed nucleus of the stria terminalis. In: Handbook of Amygdala Structure and Function; A. Rosenkranz and J. Urban (Eds.); Handbook of Behavioral Neuroscience Series, Vol. 26; Academic Press/Elsevier, London, 2020.
Martinon D, Lis P, Roman AN, Tornesi P, Applebey SV, Buechner G, Olivera V, Dabrowska J. Oxytocin receptors in the dorsolateral bed nucleus of the stria terminalis (BNST) bias fear learning toward temporally predictable cued fear. Transl Psychiatry. (2019) 9:140.
Janeček M, Dabrowska J. Oxytocin facilitates adaptive fear and attenuates anxiety responses in animal models and human studies-potential interaction with the corticotropin-releasing factor (CRF) system in the bed nucleus of the stria terminalis (BNST). Cell Tissue Res. (2019) 375:143-172.
Martinon D, Dabrowska J. Corticotropin-Releasing Factor Receptors Modulate Oxytocin Release in the Dorsolateral Bed Nucleus of the Stria Terminalis (BNST) in Male Rats. Front Neurosci. (2018) 12:183.
Ryan S, Li C, Menigoz A, Hazra R, Dabrowska J, Ehrlich D, Gordon K, Rainnie DG. Repeated shock stress facilitates basolateral amygdala synaptic plasticity through decreased cAMP-specific phosphodiesterase type IV (PDE4) expression. Brain Struct Funct. (2017) 223:1731-1745.
Moaddab M, Dabrowska J. Oxytocin receptor neurotransmission in the dorsolateral bed nucleus of the stria terminalis facilitates the acquisition of cued fear in the fear-potentiated startle paradigm in rats. Neuropharmacology. (2017) 121:130-139.
Dabrowska J, Martinon D, Moaddab M, Rainnie DG. Targeting Corticotropin-Releasing Factor Projections from the Oval Nucleus of the Bed Nucleus of the Stria Terminalis Using Cell-Type Specific Neuronal Tracing Studies in Mouse and Rat Brain. J Neuroendocrinol. (2016) Dec;28(12). doi: 10.1111/jne.12442.
Bosch OJ, Dabrowska J, Modi ME, Keebaugh AC, Barrett CE, Johnson ZV, Ahern TH, Guo JD, Grinevich V, Rainnie DG, Neumann ID, Young LJ. Oxytocin in the nucleus accumbens shell reverses CRFR2-evoked passive stress-coping after partner loss in monogamous male prairie voles. Psychoneuroendocrinology (2016) 64:66-78.
Dabrowska J, Hazra R, Guo JD, Li C, DeWitt S, Xu J, Lombroso PJ, Rainnie DG. Striatal-enriched protein tyrosine phosphatase - STEPs toward understanding chronic stress-induced activation of CRF neurons in the rat BNST. Biological Psychiatry (2013) 74:817-26.
Dabrowska J, Hazra R, Guo JD, and Rainnie DG. Central CRF neurons are not created equal: Phenotypic differences in CRF-containing neurons of the rat paraventricular hypothalamus and the bed nucleus of the stria terminalis. Frontiers in Neuroscience (2013) 7:156.
Rainnie DG, Hazra R, Dabrowska J, Guo JD, Li C, and Muly EC. Distribution and Functional Expression of Kv4 Family α Subunits and Associated KChIP β Subunits in the Bed Nucleus of the Stria Terminalis. Journal of Comparative Neurology (2014) 522:609-25.
Jasnow A, Ehrlich D, Choi D, Dabrowska J, Bowers M, Rainnie DG, Ressler KJ. Thy1-expressing neurons in the basolateral amygdala may mediate fear inhibition. Journal of Neuroscience (2013) 33:10396-404.
Hazra R, Guo JD, Dabrowska J, Rainnie DG. Differential distribution of serotonin receptor subtypes in BNST(ALG) neurons: Modulation by unpredictable shock stress. Neuroscience (2012) 225C:9-21.
Guo JD, Hazra R, Dabrowska J, Muly EC, Wess J, Rainnie DG. Presynaptic Muscarinic M2 Receptors Modulate Glutamatergic Transmission in the Bed Nucleus of the Stria Terminalis. Neuropharmacology (2012) 62:1671-83.
Li C, Dabrowska J, Hazra R, Rainnie DG. Synergistic Activation of Dopamine D1 and TrkB Receptors Mediate Gain Control of Synaptic Plasticity in the Basolateral Amygdala. PLoS One. (2011) 6(10):e26065.
Dabrowska J, Hazra R, Ahern TH, Guo JD, McDonald AJ, Mascagni F, Muller JF, Young LJ, and Rainnie DG. Neuroanatomical evidence for reciprocal regulation of the corticotrophin-releasing factor and oxytocin systems in the hypothalamus and the bed nucleus of the stria terminalis: Implications for balancing stress and affect. Psychoneuroendocrinology (2011) 36:1312-26.
Hazra R, Guo JD, Ryan SJ, Jasnow AM, Dabrowska J, Rainnie DG. A transcriptomic analysis of type I-III neurons in the bed nucleus of the stria terminalis Mol Cell Neurosci (2011) 46:699-709.
Dabrowska J and Rainnie DG. Expression and distribution of Kv4 potassium channel subunits and potassium channel interacting proteins in subpopulations of interneurons in the basolateral amygdala. Neuroscience (2010) 171:721-33.
Martin EI, Ressler KJ, Jasnow AM, Dabrowska J, Hazra R, Rainnie DG, Nemeroff CB, Owens MJ. A novel transgenic mouse for gene-targeting within cells that express corticotropin-releasing factor. Biological Psychiatry (2010) 67:1212-6.
Hammack SE, Guo JD, Hazra R, Dabrowska J, Myers KM, Rainnie DG. The response of neurons in the bed nucleus of the stria terminalis to serotonin: implications for anxiety. Prog Neuropsychopharmacol Biol Psychiatry (2009) 33:1309-20.
Dabrowska J, Nowak P, Brus R. Reactivity of 5-HT1A receptor in adult rats after neonatal noradrenergic neurons’ lesion – Implications for antidepressant-like action. Brain Res. (2008) 1239:66-76.
Nowak P, Bortel A, Dabrowska J, Biedka I, Slomian G, Roczniak W, Kostrzewa RM, Brus R. Histamine H(3) receptor ligands modulate L-dopa-evoked behavioral responses and L-dopa derived extracellular dopamine in dopamine-denervated rat striatum. Neurotox Res. (2008) 13:231-40.
Nowak P., Bortel A., Dabrowska J., Oswiecimska J., Drosik M., Kwiecinski A., Opara J., Kostrzewa RM, Brus R. Amphetamine and mCPP effects on dopamine and serotonin striatal in vivo microdialysates in an animal model of hyperactivity. Neurotox Res (2007) 11:131-44.
Dabrowska J., Nowak P., Brus R. Desensitization of 5-HT1A autoreceptors induced by neonatal DSP-4 treatment. Eur Neuropsychopharmacol (2007) 17:129-37.
Dabrowska J. and Brylinski M. Stereoselectivity of 8-OH-DPAT toward the serotonin 5- HT1A receptor: biochemical and molecular modeling study. Biochem Pharmacol (2006) 72:498-511.
Nowak P., Dabrowska J., Bortel A., Szczerbak G., Biedka I., Kostrzewa R.M., Brus R. Histamine H3 agonist- and histamine H3 antagonist-evoked vacuous chewing occurs in the absence of change in microdialysate dopamine levels. Eur J Pharmacol (2006) 552:46-54.
Ossowska K., Smialowska M., Kuter K., Wieronska J.M., Zieba B., Wardas J., Nowak P., Dabrowska J., Bortel A., Biedka I., Schulze G., Rommelspacher H. Degeneration of dopaminergic mesocortical neurons and activation of compensatory processes induced by a long-term paraquat administration in rats; implication for Parkinson’s disease. Neuroscience (2006) 141:2155-2165.
Nowak P., Dabrowska J., Bortel A., Kostrzewa R.M., Brus R. Prenatal cadmium and ethanol increase amphetamine-evoked dopamine release in rat striatum. Neurotoxicology and Teratology (2006) 28:563-72.
Nowak P, Szczerbak G, Dabrowska J, Bortel A, Biedka I, Kostrzewa RM. Molecular mechanisms of levodopa action in animal models of Parkinson's disease. Neurol Neurochir Pol. (2006) 40:517-25.
Ossowska K., Wardas J., Smialowska M., Kuter K., Lenda T., Wieronska J.M., Zieba B., Nowak P., Dabrowska J., Bortel A., Wolfarth S. A slowly developing dysfunction of dopaminergic nigrostriatal neurons induced by long-term paraquat administration in rats: an animal model of preclinical stages of Parkinson's disease? Eur J Neurosci (2005) 22:1294-1304.
Ossowska K., Wardas J., Kuter K., Nowak P., Dabrowska J., Bortel A., Labus L., Kwieciński A., Krygowska-Wajs A., Wolfarth S. Influence of paraquat on dopaminergic transporter in the rat brain. Pharmacol Rep (2005) 57:330-335.
Kuballa G., Nowak P., Bortel A., Dabrowska J., Swoboda M., Kostrzewa R.M., Brus R. Central effects of nafadotride, a dopamine D3 receptor antagonist in rats. Comparison with haloperidol and clozapine. Pharmacol Rep (2005) 57:161-169.