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Complex mechanisms govern the transport and action of oxytocin (Oxt), a neuropeptide and hormone that mediates diverse physiologic processes. While Oxt exerts site-specific and rapid effects in the brain via axonal and somatodendritic release, volume transmission via CSF and the neurovascular interface can act as an additional mechanism to distribute Oxt signals across distant brain regions on a slower timescale. This review focuses on modes of Oxt transport and action in the CNS, with particular emphasis on the roles of perivascular spaces, the blood-brain barrier (BBB), and circumventricular organs in coordinating the triadic interaction among circulating blood, CSF, and parenchyma. Perivascular spaces, critical conduits for CSF flow, play a pivotal role in Oxt diffusion and distribution within the CNS and reciprocally undergo Oxt-mediated structural and functional reconstruction. While the BBB modulates the movement of Oxt between systemic and cerebral circulation in a majority of brain regions, circumventricular organs without a functional BBB can allow for diffusion, monitoring, and feedback regulation of bloodborne peripheral signals such as Oxt. Recognition of these additional transport mechanisms provides enhanced insight into the systemic propagation and regulation of Oxt activity.

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GH acts in numerous organs expressing the GH receptor (GHR), including the brain. However, the mechanisms behind the brain's permeability to GH and how this hormone accesses different brain regions remain unclear. It is well-known that an acute GH administration induces phosphorylation of the signal transducer and activator of transcription 5 (pSTAT5) in the mouse brain. Thus, the pattern of pSTAT5 immunoreactive cells was analyzed at different time points after IP or intracerebroventricular GH injections. After a systemic GH injection, the first cells expressing pSTAT5 were those near circumventricular organs, such as arcuate nucleus neurons adjacent to the median eminence. Both systemic and central GH injections induced a medial-to-lateral pattern of pSTAT5 immunoreactivity over time because GH-responsive cells were initially observed in periventricular areas and were progressively detected in lateral brain structures. Very few choroid plexus cells exhibited GH-induced pSTAT5. Additionally, Ghr mRNA was poorly expressed in the mouse choroid plexus. In contrast, some tanycytes lining the floor of the third ventricle expressed Ghr mRNA and exhibited GH-induced pSTAT5. The transport of radiolabeled GH into the hypothalamus did not differ between wild-type and dwarf Ghr knockout mice, indicating that GH transport into the mouse brain is GHR independent. Also, single-photon emission computed tomography confirmed that radiolabeled GH rapidly reaches the ventral part of the tuberal hypothalamus. In conclusion, our study provides novel and valuable information about the pattern and mechanisms behind GH transport into the mouse brain.

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Neurogenesis continues throughout adulthood in the subventricular zone, hippocampal subgranular zone, and the hypothalamic median eminence (ME) and the adjacent medio-basal hypothalamus. The ME is one of the circumventricular organs (CVO), which are specialized brain areas characterized by an incomplete blood-brain barrier and, thus, are involved in mediating communication between the central nervous system and the periphery. Additional CVOs include the organum vasculosum laminae terminalis (OVLT) and the subfornical organs (SFO). Previous studies have demonstrated that the ME contains neural stem cells (NSCs) capable of generating new neurons and glia in the adult brain. However, it remains unclear whether the OVLT and SFO also contain proliferating cells, the identity of these cells, and their ability to differentiate into mature neurons. Here we show that glial and mural subtypes exhibit NSC characteristics, expressing the endogenous mitotic maker Ki67, and incorporating the exogenous mitotic marker BrdU in the OVLT and SFO of adult rats. Glial cells constitutively proliferating in the SFO comprise NG2 glia, while in the OVLT, both NG2 glia and tanycytes appear to constitute the NSC pool. Furthermore, pericytes, which are mural cells associated with capillaries, also contribute to the pool of cells constitutively proliferating in the OVLT and SFO of adult rats. In addition to these glial and mural cells, a fraction of NSCs containing proliferation markers Ki67 and BrdU also expresses the early postmitotic neuronal marker doublecortin, suggesting that these CVOs comprise newborn neurons. Notably, these neurons can differentiate and express the mature neuronal marker NeuN. These findings establish the sensory CVOs OVLT and SFO as additional neurogenic niches, where the generation of new neurons and glia persists in the adult brain.

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Neural progenitor cells (NPCs) are multipotent neural stem cells (NSCs) capable of self-renewing and differentiating into neurons, astrocytes and oligodendrocytes. In the postnatal/adult brain, NPCs are primarily located in the subventricular zone (SVZ) of the lateral ventricles (LVs) and subgranular zone (SGZ) of the hippocampal dentate gyrus (DG). There is evidence that NPCs are also present in the postnatal/adult hypothalamus, a highly conserved brain region involved in the regulation of core homeostatic processes, such as feeding, metabolism, reproduction, neuroendocrine integration and autonomic output. In the rodent postnatal/adult hypothalamus, NPCs mainly comprise different subtypes of tanycytes lining the wall of the 3rd ventricle. In the postnatal/adult human hypothalamus, the neurogenic niche is constituted by tanycytes at the floor of the 3rd ventricle, ependymal cells and ribbon cells (showing a gap-and-ribbon organization similar to that in the SVZ), as well as suprachiasmatic cells. We speculate that in the postnatal/adult human hypothalamus, neurogenesis occurs in a highly complex, exquisitely sophisticated neurogenic niche consisting of at least four subniches; this structure has a key role in the regulation of extrahypothalamic neurogenesis, and hypothalamic and extrahypothalamic neural circuits, partly through the release of neurotransmitters, neuropeptides, extracellular vesicles (EVs) and non-coding RNAs (ncRNAs).

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BACKGROUND: Salt-sensitive hypertension in humans and experimental models is associated with higher plasma and cerebrospinal fluid sodium chloride (NaCl) concentrations. Changes in extracellular NaCl concentrations are sensed by specialized neurons in the organum vasculosum of the lamina terminalis (OVLT). Stimulation of OVLT neurons increases sympathetic nerve activity (SNA) and arterial blood pressure (ABP), whereas chronic activation produces hypertension. Therefore, the present study tested whether OVLT neuronal activity was elevated and contributed to SNA and ABP in salt-sensitive hypertension. METHODS: Male Dahl salt-sensitive (Dahl S) and Dahl salt-resistant (Dahl R) rats were fed 0.1% or 4.0% NaCl diets for 3 to 4 weeks and used for single-unit recordings of OVLT neurons or simultaneous recording of multiple sympathetic nerves during pharmacological inhibition of the OVLT. RESULTS: Plasma and cerebrospinal fluid Na+ and Cl- concentrations were higher in Dahl S rats fed 4% versus 0.1% or Dahl R rats fed either diet. In vivo single-unit recordings revealed a significantly higher discharge of NaCl-responsive OVLT neurons in Dahl S rats fed 4% versus 0.1% or Dahl R rats. Interestingly, intracarotid infusion of hypertonic NaCl evoked greater increases in OVLT neuronal discharge of Dahl S versus Dahl R rats regardless of NaCl diet. The activity of non-NaCl-responsive OVLT neurons was not different across strain or diets. Finally, inhibition of OVLT neurons by local injection of the gamma-aminobutyric acid agonist muscimol produced a greater decrease in renal SNA, splanchnic SNA, and ABP of Dahl S rats fed 4% versus 0.1% or Dahl R rats. CONCLUSIONS: A high salt diet activates NaCl-responsive OVLT neurons to increase SNA and ABP in salt-sensitive hypertension.

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OBJECTIVES: In patients with RA, baricitinib not only improves arthritis symptom severity, but also patients' neuropsychological symptoms, such as depression and fatigue. However, the cellular mechanisms through which baricitinib can affect neural activity is unexplored. While the blood-brain barrier (BBB) permeability of this drug remains unclear, Janus kinase inhibitors (JAKi) might reach the area postrema, which is a unique brain region with a weak BBB function. Our recent study demonstrated microglial activation during experimental arthritis in the area postrema. Therefore, we sought to assess the effect of baricitinib on microglia in the area postrema using the CIA mouse model. METHODS: Microglia number and morphology in the area postrema were assessed by immunostaining for ionized calcium-binding adaptor molecule-1 (Iba-1). Data were collected on post-immunization day 35 (early phase) and 84 (late phase), and compared between baricitinib- and vehicle-treated mice. The effect on signal transducers and activators of transcription (STAT3) in the area postrema was also immunohistochemically examined. Behavioural outcomes were assessed by examining feeding behaviours and sucrose preference tests. RESULTS: In the early phase, activated microglial levels in the area postrema were decreased by baricitinib, accompanied by the inhibition of phosphorylated-STAT3 and recovery of food intake and sucrose preference. On the other hand, baricitinib did not affect microglial morphology in the late phase. CONCLUSION: Our results demonstrate that baricitinib can affect brain cells, specifically microglia, in the brain region with a weak BBB and mitigate aberrant behaviours during autoimmune arthritis, pointing to the potential therapeutic effect of JAKi on brain pathologies underpinning RA.

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The brain ventricular system (BVS) consists of brain ventricles and channels filled with cerebrospinal fluid (CSF). Disturbance of CSF flow has been linked to scoliosis and neurodegenerative diseases, including hydrocephalus. This could be due to defects of CSF production by the choroid plexus or impaired CSF movement over the ependyma dependent on motile cilia. Most vertebrates have horizontal body posture. They retain additional evolutionary innovations assisting CSF flow, such as the Reissner fiber. The causes of hydrocephalus have been studied using animal models including rodents (mice, rats, hamsters) and zebrafish. However, the horizontal body posture reduces the effect of gravity on CSF flow, which limits the use of mammalian models for scoliosis. In contrast, fish swim against the current and experience a forward-to-backward mechanical force akin to that caused by gravity in humans. This explains the increased popularity of the zebrafish model for studies of scoliosis. "Slit-ventricle" syndrome is another side of the spectrum of BVS anomalies. It develops because of insufficient inflation of the BVS. Recent advances in zebrafish functional genetics have revealed genes that could regulate the development of the BVS and CSF circulation. This review will describe the BVS of zebrafish, a typical teleost, and vertebrates in general, in comparative perspective. It will illustrate the usefulness of the zebrafish model for developmental studies of the choroid plexus (CP), CSF flow and the BVS.

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INTRODUCTION: Ghrelin regulates a variety of functions by acting in the brain. The targets of ghrelin in the mouse brain have been mainly mapped using immunolabeling against c-Fos, a transcription factor used as a marker of cellular activation, but such analysis has several limitations. Here, we used positron emission tomography in mice to investigate the brain areas responsive to ghrelin. METHODS: We analyzed in male mice the brain areas responsive to systemically injected ghrelin using positron emission tomography imaging of 18F-fluoro-2-deoxyglucose (18F-FDG) uptake, an indicator of metabolic rate. Additionally, we studied if systemic administration of fluorescent ghrelin or native ghrelin displays symmetric accessibility or induction of c-Fos, respectively, in the brain of male mice. RESULTS: Ghrelin increased 18F-FDG uptake in few specific areas of the isocortex, striatum, pallidum, thalamus, and midbrain at 0-10-min posttreatment. At the 10-20 and 20-30 min posttreatment, ghrelin induced mixed changes in 18F-FDG uptake in specific areas of the isocortex, striatum, pallidum, thalamus, and midbrain, as well as in areas of the olfactory areas, hippocampal and retrohippocampal regions, hypothalamus, pons, medulla, and even the cerebellum. Ghrelin-induced changes in 18F-FDG uptake were transient and asymmetric. Systemically administrated fluorescent-ghrelin-labeled midline brain areas known to contain fenestrated capillaries and the hypothalamic arcuate nucleus, where a symmetric labeling was observed. Ghrelin treatment also induced a symmetric increased c-Fos labeling in the arcuate nucleus. DISCUSSION/CONCLUSION: Systemically injected ghrelin transiently and asymmetrically affects the metabolic activity of the brain of male mice in a wide range of areas, in a food intake-independent manner. The neurobiological bases of such asymmetry seem to be independent of the accessibility of ghrelin into the brain.

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Microglia are involved in neuroinflammatory processes during diverse pathophysiological conditions. To date, the possible contribution of these cells to deoxynivalenol (DON)-induced brain inflammation and anorexia has not yet been evaluated. DON, one of the most abundant trichothecenes found in cereals, has been implicated in mycotoxicosis in both humans and farm animals. DON-induced toxicity is characterized by reduced food intake, weight gain, and immunological effects. We previously showed that exposure to DON induces an inflammatory response within the hypothalamus and dorsal vagal complex (DVC) which contributes to DON-induced anorexia. Here, in response to anorectic DON doses, we reported microglial activation within two circumventricular organs (CVOs), the area postrema (AP) and median eminence (ME) located in the DVC and the hypothalamus, respectively. Interestingly, this microglial activation was observed while DON-induced anorexia was ongoing (i.e., 3 and 6 h after DON administration). Next, we took advantage of pharmacological microglia deletion using PLX3397, a colony-stimulating factor 1 receptor (CSF1R)-inhibitor. Surprisingly, microglia-depleted mice exhibited an increased sensitivity to DON since non-anorectic DON doses reduced food intake in PLX3397-treated mice. Moreover, low DON doses induced c-Fos expression within feeding behavior-associated structures in PLX3397-treated mice but not in control mice. In parallel, we have highlighted heterogeneity in the phenotype of microglial cells present in and around the AP and ME of control animals. In these areas, microglial subpopulations expressed IBA1, TMEM119, CD11b and CD68 to varying degrees. In addition, a CD68 positive subpopulation showed, under resting conditions, a noticeable phagocytotic/endocytotic activity. We observed that DON strongly reduced CD68 in the hypothalamus and DVC. Finally, inactivation of constitutively active microglia by intraperitoneal administration of minocycline resulted in anorexia with a DON dose ineffective in control mice. Taken together, these results strongly suggest that various populations of microglial cells residing in and around the CVOs are maintained in a functionally active state even under physiological conditions. We propose that these microglial cell populations are attempting to protect the brain parenchyma from hazardous molecules coming from the blood. This study could contribute to a better understanding of how microglia respond to environmental contaminants.

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The circumventricular organs (CVOs) are unique areas within the central nervous system. They serve as a portal for the rest of the body and, as such, lack a blood-brain barrier. Microglia are the primary resident immune cells of the brain parenchyma. Within the CVOs, microglial cells find themselves continuously challenged and stimulated by local and systemic stimuli, even under steady-state conditions. Therefore, CVO microglia in their typical state often resemble the activated microglial forms found elsewhere in the brain as they are responding to pathological conditions or other stressors. In this review, I focus on the dynamics of CVO microglia, using the pineal gland as a specific CVO example. Data related to microglia heterogeneity in both homeostatic and unhealthy environments are presented and discussed, including those recently generated by using advanced single-cell and single-nucleus technology. Finally, perspectives in the CVO microglia field are also included.Summary StatementMicroglia in circumventricular organs (CVOs) continuously adapt to react differentially to the diverse challenges they face. Herein, I discuss microglia heterogeneity in CVOs, including pineal gland. Further studies are needed to better understand microglia dynamics in these unique brain areas. .

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Sensory circumventricular organs (sCVOs) are pivotal brain structures involved in immune-to-brain communication with a leaky blood-brain barrier that detect circulating mediators such as lipopolysaccharide (LPS). Here, we aimed to investigate the potential of sCVOs to produce n-3 and n-6 oxylipins after LPS-stimulation. Moreover, we investigated if norepinephrine (NE) co-treatment can alter cytokine- and oxylipin-release. Thus, we stimulated rat primary neuroglial sCVO cultures under n-3- or n-6-enriched conditions with LPS or saline combined with NE or vehicle. Supernatants were assessed for cytokines by bioassays and oxylipins by HPLC-MS/MS. Expression of signaling pathways and enzymes were analyzed by RT-PCR. Tumor necrosis factor (TNF)α bioactivity and signaling, IL-10 expression, and cyclooxygenase (COX)2 were increased, epoxide hydroxylase (Ephx)2 was reduced, and lipoxygenase 15-(LOX) was not changed by LPS stimulation. Moreover, LPS induced increased levels of several n-6-derived oxylipins, including the COX-2 metabolite 15d-prostaglandin-J2 or the Ephx2 metabolite 14,15-DHET. For n-3-derived oxylipins, some were down- and some were upregulated, including 15-LOX-derived neuroprotectin D1 and 18-HEPE, known for their anti-inflammatory potential. While the LPS-induced increase in TNFα levels was significantly reduced by NE, oxylipins were not significantly altered by NE or changes in TNFα levels. In conclusion, LPS-induced oxylipins may play an important functional role in sCVOs for immune-to-brain communication.

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During development, the central nervous system (CNS) vasculature grows to precisely meet the metabolic demands of neurons and glia. In addition, the vast majority of the CNS vasculature acquires a unique set of molecular and cellular properties-collectively referred to as the blood-brain barrier-that minimize passive diffusion of molecules between the blood and the CNS parenchyma. Both of these processes are controlled by signals emanating from neurons and glia. In this review, we describe the nature and mechanisms-of-action of these signals, with an emphasis on vascular endothelial growth factor (VEGF) and beta-catenin (canonical Wnt) signaling, the two best-understood systems that regulate CNS vascular development. We highlight foundational discoveries, interactions between different signaling systems, the integration of genetic and cell biological studies, advances that are of clinical relevance, and questions for future research.

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The "astrocyte-to-neuron lactate shuttle" (ANLS) mechanism is part of the central inhibitory pathway to modulate sodium intake. An interaction between the GABAergic neurons and nitric oxide (NO) in the subfornical organ (SFO) in salt-appetite inhibition has been suggested. In addition, NO is a key molecule involved in astrocytic energy metabolism and lactate production. In the present study, we hypothesized there is an interaction between astrocytic lactate and central NO to negatively modulate water and sodium intake through the ANLS mechanism. The results showed that central Nω-nitro-L-arginine methyl ester (L-NAME, NO-synthase inhibition) induced an increase in water and sodium intake. These responses were attenuated by previous central microinjection of fluorocitrate (FCt, a reversible glial inhibitor). Interestingly, L-NAME-induced water and sodium intake were also decreased by previous microinjection of lactate but did not change after inhibition of the ANLS mechanism by α-cyano 4-hydroxycinnamic acid (α-CHCA), an inhibitor of the MCT lactate transporter. Our results suggest a central interaction between NO, glial cells, and lactate to modulate water and sodium intake.

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The SARS-CoV-2 virus gains entry to cells by binding to angiotensin-converting enzyme 2 (ACE2). Since circumventricular organs and parts of the hypothalamus lack a blood-brain barrier, and immunohistochemical studies demonstrate that ACE2 is highly expressed in circumventricular organs which are intimately connected to the hypothalamus, and the hypothalamus itself, these might be easy entry points for SARS-CoV-2 into the brain via the circulation. High ACE2 protein expression is found in the subfornical organ, area postrema, and the paraventricular nucleus of the hypothalamus (PVH). The subfornical organ and PVH are parts of a circuit to regulate osmolarity in the blood, through the secretion of anti-diuretic hormone into the posterior pituitary. The PVH is also the stress response centre in the brain. It controls not only pre-ganglionic sympathetic neurons, but is also a source of corticotropin-releasing hormone, that induces the secretion of adrenocorticotropic hormone from the anterior pituitary. It is proposed that the function of ACE2 in the circumventricular organs and the PVH could be diminished by binding with SARS-CoV-2, thus leading to a reduction in the ACE2/Ang (1-7)/Mas receptor (MasR) signalling axis, that modulates ACE/Ang II/AT1R signalling. This could result in increased presympathetic activity/neuroendocrine secretion from the PVH, and effects on the hypothalamic-pituitary-adrenal axis activity. Besides the bloodstream, the hypothalamus might also be affected by SARS-CoV-2 via transneuronal spread along the olfactory/limbic pathways. Exploring potential therapeutic pathways to prevent or attenuate neurological symptoms of COVID-19, including drugs which modulate ACE signalling, remains an important area of unmet medical need.

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Circumventricular organs (CVOs), including the mediobasal hypothalamus (MBH), have an incomplete blood-brain barrier (BBB). In this study, we determined if the BBB function in the MBH is modulated by the gut microbiota or by the Toll-like receptor (TLR) adapter proteins TRIF or MyD88 signaling. By injecting mice with Evans blue, a marker for BBB permeability, we show that germ-free (GF) and conventionally raised (CONV-R) mice did not differ in the number of Evans blue-positive cells in MBH. Acute modulation of the gut microbiota did not change the number of Evans blue-positive cells. In contrast, CONV-R Myd88-/- and Trif-/- mice had a reduced number of cells in direct contact to the circulation compared to wildtype (WT) mice. This was accompanied by increased tight junction proteins in the blood vessels in Myd88-/- mice. To further characterize the BBB function, we injected WT and Myd88 -/- CONV-R mice as well as WT GF mice with monosodium glutamate (MSG), a neurotoxin that does not cross the BBB. While MSG caused vast cell death in the MBH in CONV-R and GF WT mice, Myd88 -/- mice were protected from such cell death suggesting that fewer cells are exposed to the neurotoxin in the Myd88 -/- mice. Taken together, our results suggest that MyD88 deficiency, but not gut microbiota depletion, is sufficient to modulate the BBB function in the MBH.

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The blood-brain barrier (BBB) protects the vertebrate central nervous system from harmful blood-borne, endogenous and exogenous substances to ensure proper neuronal function. The BBB describes a function that is established by endothelial cells of CNS vessels in conjunction with pericytes, astrocytes, neurons and microglia, together forming the neurovascular unit (NVU). Endothelial barrier function is crucially induced and maintained by the Wnt/ß-catenin pathway and requires intact NVU for proper functionality. The BBB and the NVU are characterized by a specialized assortment of molecular specializations, providing the basis for tightening, transport and immune response functionality.The present chapter introduces state-of-the-art knowledge of BBB structure and function and highlights current research topics, aiming to understanding in more depth the cellular and molecular interactions at the NVU, determining functionality of the BBB in health and disease, and providing novel potential targets for therapeutic BBB modulation. Moreover, we highlight recent advances in understanding BBB and NVU heterogeneity within the CNS as well as their contribution to CNS physiology, such as neurovascular coupling, and pathophysiology, is discussed. Finally, we give an outlook onto new avenues of BBB research.

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Evidence on adult mammalian neurogenesis and scarce studies with human brains led to the idea that adult human neurogenesis occurs in the subgranular zone (SGZ) of the dentate gyrus and in the subventricular zone (SVZ). However, findings published from 2018 rekindled controversies on adult human SGZ neurogenesis. We systematically reviewed studies published during the first decade of characterization of adult human neurogenesis (1994-2004) - when the two-neurogenic-niche concept in humans was consolidated - and compared with further studies. The synthesis of both periods is that adult human neurogenesis occurs in an intensity ranging from practically zero to a level comparable to adult mammalian neurogenesis in general, which is the prevailing conclusion. Nonetheless, Bernier and colleagues showed in 2000 intriguing indications of adult human neurogenesis in a broad area including the limbic system. Likewise, we later showed evidence that limbic and hypothalamic structures surrounding the circumventricular organs form a continuous zone expressing neurogenesis markers encompassing the SGZ and SVZ. The conclusion is that publications from 2018 on adult human neurogenesis did not bring novel findings on location of neurogenic niches. Rather, we expect that the search of neurogenesis beyond the canonical adult mammalian neurogenic niches will confirm our indications that adult human neurogenesis is orchestrated in a broad brain area. We predict that this approach may, for example, clarify that human hippocampal neurogenesis occurs mostly in the CA1-subiculum zone and that the previously identified human rostral migratory stream arising from the SVZ is indeed the column of the fornix expressing neurogenesis markers.

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The blood-brain barrier (BBB) is essential for creating and maintaining tissue homeostasis in the central nervous system (CNS), which is key for proper neuronal function. In most vertebrates, the BBB is localized to microvascular endothelial cells that acquire barrier properties during angiogenesis of the neuroectoderm. Complex and continuous tight junctions, and the lack of fenestrae combined with low pinocytotic activity render the BBB endothelium a tight barrier for water-soluble molecules that may only enter the CNS via specific transporters. The differentiation of these unique endothelial properties during embryonic development is initiated by endothelial-specific flavours of the Wnt/ß-catenin pathway in a precise spatiotemporal manner. In this review, we summarize the currently known cellular (neural precursor and endothelial cells) and molecular (VEGF and Wnt/ß-catenin) mechanisms mediating brain angiogenesis and barrier formation. Moreover, we introduce more recently discovered crosstalk with cellular and acellular elements within the developing CNS such as the extracellular matrix. We discuss recent insights into the downstream molecular mechanisms of Wnt/ß-catenin in particular, the recently identified target genes like Foxf2, Foxl2, Foxq1, Lef1, Ppard, Zfp551, Zic3, Sox17, Apcdd1 and Fgfbp1 that are involved in refining and maintaining barrier characteristics in the mature BBB endothelium. Additionally, we elute to recent insight into barrier heterogeneity and differential endothelial barrier properties within the CNS, focussing on the circumventricular organs as well as on the neurogenic niches in the subventricular zone and the hippocampus. Finally, open questions and future BBB research directions are highlighted in the context of taking benefit from understanding BBB development for strategies to modulate BBB function under pathological conditions.

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Vasopressin (AVP) is a key neurohormone involved in the regulation of body functions. Due to its urine-concentrating effect in the kidneys, it is often referred to as antidiuretic hormone. Besides its antidiuretic renal effects, AVP is a potent neurohormone involved in the regulation of arterial blood pressure, sympathetic activity, baroreflex sensitivity, glucose homeostasis, release of glucocorticoids and catecholamines, stress response, anxiety, memory, and behavior. Vasopressin is synthesized in the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus and released into the circulation from the posterior lobe of the pituitary gland together with a C-terminal fragment of pro-vasopressin, known as copeptin. Additionally, vasopressinergic neurons project from the hypothalamus to the brainstem nuclei. Increased release of AVP into the circulation and elevated levels of its surrogate marker copeptin are found in pulmonary diseases, arterial hypertension, heart failure, obstructive sleep apnoea, severe infections, COVID-19 due to SARS-CoV-2 infection, and brain injuries. All these conditions are usually accompanied by respiratory disturbances. The main stimuli that trigger AVP release include hyperosmolality, hypovolemia, hypotension, hypoxia, hypoglycemia, strenuous exercise, and angiotensin II (Ang II) and the same stimuli are known to affect pulmonary ventilation. In this light, we hypothesize that increased AVP release and changes in ventilation are not coincidental, but that the neurohormone contributes to the regulation of the respiratory system by fine-tuning of breathing in order to restore homeostasis. We discuss evidence in support of this presumption. Specifically, vasopressinergic neurons innervate the brainstem nuclei involved in the control of respiration. Moreover, vasopressin V1a receptors (V1aRs) are expressed on neurons in the respiratory centers of the brainstem, in the circumventricular organs (CVOs) that lack a blood-brain barrier, and on the chemosensitive type I cells in the carotid bodies. Finally, peripheral and central administrations of AVP or antagonists of V1aRs increase/decrease phrenic nerve activity and pulmonary ventilation in a site-specific manner. Altogether, the findings discussed in this review strongly argue for the hypothesis that vasopressin affects ventilation both as a blood-borne neurohormone and as a neurotransmitter within the central nervous system.

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In the laboratory, animals' motivation to work tends to be positively correlated with reward magnitude. But in nature, rewards earned by work are essential to survival (e.g., working to find water), and the payoff of that work can vary on long timescales (e.g., seasonally). Under these constraints, the strategy of working less when rewards are small could be fatal. We found that instead, rats in a closed economy did more work for water rewards when the rewards were stably smaller, a phenomenon also observed in human labor supply curves. Like human consumers, rats showed elasticity of demand, consuming far more water per day when its price in effort was lower. The neural mechanisms underlying such "rational" market behaviors remain largely unexplored. We propose a dynamic utility maximization model that can account for the dependence of rat labor supply (trials/day) on the wage rate (milliliter/trial) and also predict the temporal dynamics of when rats work. Based on data from mice, we hypothesize that glutamatergic neurons in the subfornical organ in lamina terminalis continuously compute the instantaneous marginal utility of voluntary work for water reward and causally determine the amount and timing of work.

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