Biology subjects

Dabrowska, J.

Publications and source records attributed to Dabrowska, J..

4 recordsLinked to original sources

bioRxiv2024

Corticotropin-releasing factor neurons of the bed nucleus of the stria terminalis demonstrate sex- and estrous phase-dependent differences in synaptic activity and in their role in anxiety-potentiated startle

BackgroundThe prevalence of post-traumatic stress disorder (PTSD) and anxiety disorders is higher in women than men. The severity of hallmark symptoms including hypervigilance and fear reactivity to unpredictable threats varies with sex and reproductive cycle, but the underlying mechanisms remain unclear. Here, we investigated corticotropin-releasing factor (CRF) neurons in the dorsolateral bed nucleus of the stria terminalis (BNSTDL) as a potential nexus for the influence of biological sex and reproductive cycle on fear- and anxiety-related behaviors. Methods103 male and 132 cycle-monitored female CRF-Cre rats were used. BNSTDL-CRF neuron excitability and synaptic activity was recorded with slice electrophysiology. Chemogenetic inhibition of BNSTDL-CRF neurons was performed before elevated-plus maze, predator odor exposure, shock-induced startle sensitization, and anxiety-potentiated startle (APS) following unpredictable fear conditioning. ResultsBNSTDL-CRF neurons in females exhibit higher excitability (cycle-independent) and lower sensitivity to excitatory synaptic inputs (proestrus and diestrus) compared to males. BNSTDL-CRF neuron inhibition reduces open-arm time in estrous females but not males, suggesting that BNSTDL-CRF neurons reduce anxiety during sexual receptivity. In the APS, BNSTDL-CRF neuron inhibition attenuates short-term startle potentiation in males, whereas it causes persistent APS in diestrous females. ConclusionsUnpredictable fear conditioning elicits sex- and estrous phase-specific APS, differentially regulated by BNSTDL-CRF neurons. Persistent APS in females align with hormonal phases marked by low reproductive hormones, mirroring human PTSD findings. Our findings underscore the sex- and hormone-specific role of BNSTDL-CRF neurons in APS. Widely used in human studies, APS may bridge animal and human research, supporting biomarker development and more effective pharmacotherapies.

neuroscience↗

bioRxiv2024

Like sisters but not twins - vasopressin and oxytocin excite BNST neurons via cell type-specific expression of oxytocin receptor to reduce anxious arousal

Interoceptive signals dynamically interact with the environment to shape appropriate defensive behaviors. Hypothalamic hormones arginine-vasopressin (AVP) and oxytocin (OT) regulate physiological states, including water and electrolyte balance, circadian rhythmicity, and defensive behaviors. Both AVP and OT neurons project to dorsolateral bed nucleus of stria terminalis (BNSTDL), which expresses oxytocin receptors (OTR) and vasopressin receptors and mediates fear responses. However, understanding the integrated role of neurohypophysial hormones is complicated by the cross-reactivity of AVP and OT and their mutual receptor promiscuity. Here, we provide evidence that the effects of neurohypophysial hormones on BNST excitability are driven by input specificity and cell type-specific receptor selectivity. We show that OTR-expressing BNSTDL neurons, excited by hypothalamic OT and AVP inputs via OTR, play a major role in regulating BNSTDL excitability, overcoming threat avoidance, and reducing threat-elicited anxious arousal. Therefore, OTR-BNSTDL neurons are perfectly suited to drive the dynamic interactions balancing external threat risk and physiological needs. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/611656v2_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@2c800forg.highwire.dtl.DTLVardef@18b5cfaorg.highwire.dtl.DTLVardef@85324aorg.highwire.dtl.DTLVardef@a8bb6b_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIExogenous and light-evoked vasopressin (AVP) peptide excites neurons of the bed nucleus of the stria terminalis (BNST) via oxytocin receptor (OTR) in male rats C_LIO_LIAVP excites OTR- and Corticotropin-releasing factor (CRF)-expressing neurons, most of which are classified as Type III neurons of the BNST C_LIO_LIOTR-expressing BNST neurons increase exploration of open spaces and reduce anxious arousal in fear-potentiated startle in male rats C_LIO_LIThe dorsolateral BNST receives vasopressinergic inputs from suprachiasmatic, supraoptic, and paraventricular nuclei of the hypothalamus C_LIO_LIInternal signal-sensitive hypothalamic inputs directly impact BNST excitability via OTR to balance interoceptive signals and defensive behaviors C_LI

neuroscience↗

bioRxiv2023

Fear-conditioning to unpredictable threats reveals sex differences in rat fear-potentiated startle (FPS)

Fear-potentiated startle (FPS) has been widely used to study fear processing in humans and rodents. Human studies have shown higher startle amplitudes and exaggerated fear reactivity to unpredictable vs. predictable threats in individuals suffering from post-traumatic stress disorder (PTSD). Although human FPS studies often use both sexes, a surprisingly limited number of rodent FPS studies use females. Here we investigate the effects of signal-threat contingency, signal-threat order and threat predictability on FPS in both sexes. We use a classic fear-conditioning protocol (100% contingency of cue and shock pairings, with forward conditioning such that the cue co-terminates with the shock) and compare it to modified fear-conditioning protocols (70% contingency; backward conditioning; or cue and shock unpaired). Although there are no sex differences in the startle amplitudes when corrected for body weight, females demonstrate higher shock reactivity during fear-conditioning. Both sexes demonstrate comparable levels of cued, non-cued, and contextual fear in the classic FPS but females show reduced fear discrimination vs. males. Fear-conditioning with 70% contingency or backward order (cue co-starts with shock) induces similar levels of cued, non-cued, and contextual fear in both sexes but they differ in contextual fear extinction. Lastly, a prominent sex difference is uncovered following unpredictable fear-conditioning protocol (cue and shock un-paired), with females showing significantly higher startle overall during the FPS recall, regardless of trial type, and higher contextual fear 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. HighlightsO_LIMale and female rats have comparable startle amplitudes when corrected for body weight C_LIO_LIFemale rats show higher foot-shock reactivity than males during fear-conditioning C_LIO_LIFemale rats show reduced fear discrimination vs. males in the classic FPS C_LIO_LIReversed signal-threat order increases contextual fear in both sexes C_LIO_LIExposure to unpredictable threats increases startle in general and contextual fear only in females C_LI

neuroscience↗

bioRxiv2020

Oxytocin selectively excites interneurons and inhibits output neurons of the bed nucleus of the stria terminalis (BNST)

The dorsolateral bed nucleus of the stria terminalis (BNSTDL) has high expression of oxytocin (OT) receptors (OTR), which were shown to facilitate cued fear. However, the role of OTR in the modulation of BNSTDL activity remains elusive. BNSTDL contains GABA-ergic neurons classified based on intrinsic membrane properties into three types. Using in vitro patch-clamp recordings in male rats, we demonstrate that OT selectively excites and increases spontaneous firing rate of Type I BNSTDL neurons. As a consequence, 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, and reduces spontaneous firing rate in these neurons. These results suggest an indirect effect of OT in Type II neurons, which is mediated via OT-induced increase in firing of Type I interneurons. As Type II BNSTDL neurons were shown projecting to the central amygdala (CeA), we also recorded from retrogradelly labeled BNST[->]CeA neurons and we show that OT increases the frequency of sIPSC in these Type II BNST[->]CeA output neurons. In contrast, in Type III neurons, OT reduces the amplitude, but not frequency, of both sIPSCs and evoked IPSCs via a postsynaptic mechanism without changing their intrinsic excitability. We present a model of fine-tuned modulation of BNSTDL activity by OT, which selectively excites BNSTDL interneurons and inhibits Type II BNST[->]CeA output neurons. These results suggest that OTR in the BNST might facilitate cued fear by inhibiting the BNST[->]CeA neurons. HighlightsO_LIOxytocin directly excites and increases spontaneous firing of Type I BNST interneurons C_LIO_LIOxytocin indirectly inhibits Type II BNST neurons C_LIO_LIOxytocin inhibits Type II BNST output neurons to the central amygdala (BNST[->]CeA) C_LIO_LIOxytocin reduces GABA-ergic transmission in Type III BNST neurons C_LIO_LIOxytocin might facilitate cued fear by inhibiting the Type II BNST[->]CeA neurons C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=174 HEIGHT=200 SRC="FIGDIR/small/169466v3_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@134326dorg.highwire.dtl.DTLVardef@1dad252org.highwire.dtl.DTLVardef@1263dd6org.highwire.dtl.DTLVardef@1a5c9e9_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗