Oxytocin (OT) is a hypothalamic neuropeptide that modulates fear and anxiety-like behaviors. Dorsolateral bed nucleus of the stria terminalis (BNSTdl) plays a critical role in the regulation of fear and anxiety, and expresses high levels of OT receptor (OTR). However, the role of OTR neurotransmission within the BNSTdl in mediating these behaviors is unknown. Here, we used adult male Sprague-Dawley rats to investigate the role of OTR neurotransmission in the BNSTdl in the modulation of the acoustic startle response, as well as in the acquisition and consolidation of conditioned fear using fear potentiated startle (FPS) paradigm. Bilateral intra-BNSTdl administration of OT (100 ng) did not affect the acquisition of conditioned fear response. However, intra-BNSTdl administration of specific OTR antagonist (OTA), (d(CH2)51, Tyr(Me)2, Thr4, Orn8, des-Gly-NH29)-vasotocin, (200 ng), prior to the fear conditioning session, impaired the acquisition of cued fear, without affecting a non-cued fear component of FPS. Neither OTA, nor OT affected baseline startle or shock reactivity during fear conditioning. Therefore, the observed impairment of cued fear after OTA infusion resulted from the specific effect on the formation of cued fear. In contrast to the acquisition, neither OTA nor OT affected the consolidation of FPS, when administered after the completion of fear conditioning session. Taken together, these results reveal the important role of OTR neurotransmission in the BNSTdl in the formation of conditioned fear to a discrete cue. This study highlights the role of the BNSTdl in learning to discriminate between threatening and safe stimuli.

The bed nucleus of the stria terminalis (BNST) is known to play a critical role in mediating the behavioral and autonomic responses to stressors. The oval nucleus of the BNST (BNSTov) contains cell bodies that synthesize the stress hormone, corticotropin releasing factor (CRF). Although afferent fibers originating from the BNSTov have been shown to innervate several key structures of the neuroendocrine and central autonomic system, the question remains as to whether, some of these fibers are CRF-positive. To directly address this question, we injected a “floxed” anterograde tracer (rAAV5/EF1a-DIO-mCherry) into the BNSTov of CRFp3.0CreGFP transgenic mice, which express a green fluorescent protein (GFP) under the control of the CRF promoter. Serial sections were then analyzed for the presence of double-labeled fibers in potential projection sites. To determine whether CRF neurons in the rat BNSTov send comparable projections, we infused rat BNSTov with an AAV in which the human synapsin promoter drives enhanced GFP expression. We then used CRF immunoreactivity to examine double-labeled fluorescent fibers and axon terminals in projection sites from brain sections of the AAV-infused rats. We have observed several terminal fields in the mouse and rat brain with double-labeled fibers in the Dorsal raphe nucleus (DRD), the Paraventricular nucleus of the hypothalamus, and to a lesser extent in the Ventral tegmental area. We found double-labeled terminal boutons in the nucleus accumbens shell, prelimbic cortex, and posterior basolateral nucleus of the amygdala. The most intense double-labeling was found in midbrain, including substantia nigra pars compacta, red nucleus, periaqueductal gray, pontine nuclei, as well as DRD. The results of our study indicate that CRF neurons are the output neurons of the BNSTov and they send projections to the centers of neuroendocrine and autonomic regulation, but also regions modulating reward and motivation, vigilance, motor function, as well as affective behavior.

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