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Séminaire - Joanna DabrowskaRevisiting 'bad' and 'good' neuropeptides in the regulation of stress, fear, and anxiety

Abstract :

Activation of corticotropin releasing factor (CRF) neurons in the paraventricular nucleus of the hypothalamus (PVN) is necessary for establishing the classic endocrine response to stress, whereas activation of forebrain CRF neurons mediates affective components of the stress response. In a first part of my talk I will demonstrate that CRF neurons in the anterolateral cell group of the bed nucleus of the stria terminalis (BNSTALG) are sensitive to repeated restraint stress (RRS) and they express specific signal transduction factors that regulate their stress-induced synaptic plasticity. Striatal-enriched protein tyrosine phosphatase is selectively expressed in CRF neurons in the oval nucleus of the BNSTALG. Following RRS, male rats displayed an increase in anxiety-like behavior, which was associated with a down-regulation of STEP messenger RNA and protein expression in the BNSTALG. This was accompanied by selective facilitation of long-term potentiation (LTP) induced in Type III, putative CRF neurons of the BNSTALG. However, intracellular application of STEP completely blocked the RRS-induced facilitation of LTP in the putative CRF neurons of the BNST. Hence, STEP appears to protect CRF neurons from RRS-induced plasticity, but down-regulation of STEP after RRS leads to long-term plasticity and contribute to prolonged states of anxiety (Dabrowska et al., 2013). In the second part of my talk I will demonstrate that oxytocin neurons in the paraventricular nucleus of the hypothalamus (PVN) are uniquely positioned to regulate BNSTALG activity.

Oxytocin is a hormone and a neuromodulator that has been shown to attenuate stress response and reduce anxiety. We have demonstrated that oxytocin neurons from the PVN project to the BNSTALG, where oxytocinergic fibers and terminals make perisomatic contacts with local neurons, including CRF neurons. Using single-cell RT-PCR technique we also demonstrate that majority of BNSTALG neurons express oxytocin receptor (OTR) (Dabrowska et al, 2011).
However, the role of OTR in the BNSTALG in the regulation of fear and anxiety is not known. Here, in order to determine the role of OTR, we employ fear-potentiated startle (FPS) paradigm. In the FPS, an acoustic startle reflex (ASR) is significantly potentiated by an exposure to a conditioned stimulus that has been previously paired with a foot shock (unconditioned stimulus).
Here, we used in vivo pharmacology approach in male rats to determine the role of OTR neurotransmission in the BNSTALG in the acquisition and consolidation of the FPS. We demonstrate that although oxytocin does not affect baseline ASR or shock reactivity during fear conditioning, bilateral intra-BNSTALG infusion of selective OTR antagonist significantly reduces acquisition of cued-fear measured in the FPA.

In contrast, manipulation of OTR does not affect non-cued fear component of the FPS. Furthermore, the effect of OTA is specific to the acquisition phase of conditioned fear, because neither oxytocin nor OTA affected consolidation of FPS (Moaddab and Dabrowska, 2017).
These results reveal the important role of OTR neurotransmission in the BNST in the formation of conditioned fear to a discrete cue. This study also highlights the role of the BNST in learning to discriminate between threatening and safe stimuli. Finally, these studies reveal cell-type and brain-site specific roles of neuropeptides and neuromodulators that have been ‘categorized’ as purely anxiolytic or purely anxiogenic compounds. 

Selected publications

Dabrowska J, Martinon D, Moaddab M, Rainnie DG. Targeting corticotropin-releasing factor (CRF) projections from the oval nucleus of the BNST using cell-type specific neuronal tracing studies in mouse and rat brain. J Neuroendocrinol. (2016) Nov 2. doi: 10.1111/jne.12442. [Epub ahead of print]

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.