Local Corticotropin-Releasing Factor Signaling in the Hypothalamic Paraventricular Nucleus

Abstract

Corticotropin-releasing factor (CRF) neurons in the hypothalamic paraventricular nucleus (PVN) initiate hypothalamic-pituitary-adrenal axis activity through the release of CRF into the portal system as part of a coordinated neuroendocrine, autonomic, and behavioral response to stress. The recent discovery of neurons expressing CRF receptor type 1 (CRFR1), the primary receptor for CRF, adjacent to CRF neurons within the PVN, suggests that CRF also signals within the hypothalamus to coordinate aspects of the stress response. Here, we characterize the electrophysiological and molecular properties of PVN-CRFR1 neurons and interrogate their monosynaptic connectivity using rabies virus-based tracing and optogenetic circuit mapping in male and female mice. We provide evidence that CRF neurons in the PVN form synapses on neighboring CRFR1 neurons and activate them by releasing CRF. CRFR1 neurons receive the majority of monosynaptic input from within the hypothalamus, mainly from the PVN itself. Locally, CRFR1 neurons make GABAergic synapses on parvocellular and magnocellular cells within the PVN. CRFR1 neurons resident in the PVN also make long-range glutamatergic synapses in autonomic nuclei such as the nucleus of the solitary tract. Selective ablation of PVN-CRFR1 neurons in male mice elevates corticosterone release during a stress response and slows the decrease in circulating corticosterone levels after the cessation of stress. Our experiments provide evidence for a novel intra-PVN neural circuit that is activated by local CRF release and coordinates autonomic and endocrine function during stress responses. The hypothalamic paraventricular nucleus (PVN) coordinates concomitant changes in autonomic and neuroendocrine function to organize the response to stress. This manuscript maps intra-PVN circuitry that signals via CRF, delineates CRF receptor type 1 neuron synaptic targets both within the PVN and at distal targets, and establishes the role of this microcircuit in regulating hypothalamic-pituitary-adrenal axis activity.

Astrocytes Amplify Neuronal Dendritic Volume Transmission Stimulated by Norepinephrine

“…Indeed, the spatial reach of the retrograde signal could attain even greater distances if the astrocytic calcium signal was transmitted to distal astrocytes by gap junction coupling. This needs to be further studied but could explain why we saw a less robust norepinephrine facilitation of inhibitory than excitatory synaptic inputs because the presynaptic GABA neurons are thought to be located outside the PVN (Boudaba et al, 1996;Herman et al, 2004;Ulrich-Lai and Herman, 2009) (but see also Jiang et al, 2018), whereas the presynaptic glutamate neurons may be intrinsic to the PVN and, thus, more proximal to the CRH neurons (Daftary et al, 1998(Daftary et al, , 2000Wittmann et al, 2005;Hrabovszky et al, 2005Hrabovszky et al, , 2005. Consistent with a difference in the relative distances of presynaptic glutamate and GABA neurons from the CRH neurons, the facilitation of EPSCs was seen in over 90% of recorded CRH neurons, whereas the facilitation of IPSCs occurred in 55% of the neurons, suggesting that the presynaptic GABA neurons are more distal and fewer retained intact axonal projections to the CRH neurons in our slices.…”

Emotional remodeling with oxytocin durably rescues trauma-induced behavioral and neuro-morphological changes in rats: a promising treatment for PTSD

“…Oxytocin is a nonaddictive nona-peptide, which is synthesized in the paraventricular and supraoptical nuclei of the hypothalamus of vertebrates and which exerts a wide spectrum of central and peripheral effects as neurohormone, neurotransmitter, or neuromodulator 11 . In the central nervous system, it is released by two neuronal populations of the paraventricular nucleus, the magnocellular neurons which project to the posterior pituitary, and the parvocellular neurons which project on the anterior pituitary, directly into the circulation [12][13][14] . The oxytocin effects are transduced via the oxytocin receptors abundantly expressed in regions involved in emotions and cognition like the hippocampus, the septum, and the amygdala 15,16 .…”

Neural Control of Homeostatic Feeding and Food Selection

“…In contrast, injection of a CRH receptor 1 (corticotropin-releasing factor receptor 1, CRFR1) antagonist into the PVH suppressed the fasting-induced increase in HCD selection and decrease in HFD selection. CRFR1 is expressed at a high level in the PVH [70], and CRFR1-expressing neurons in this nucleus include glutamatergic and GABAergic neurons and do not express CRH, vasopressin, oxytocin, or TRH [70,71]. CRFR1-expressing neurons in the PVH control brain areas that regulate food intake and sweet taste sensing [39,68,70,72].…”