Neural cell-types and circuits linking thermoregulation and social behavior.

Understanding how social and affective behavioral states are controlled by neural circuits is a fundamental challenge in neurobiology. Despite increasing understanding of central circuits governing prosocial and agonistic interactions, how bodily autonomic processes regulate these behaviors is less resolved. Thermoregulation is vital for maintaining homeostasis, but also associated with cognitive, physical, affective, and behavioral states. Here, we posit that adjusting body temperature may be integral to the appropriate expression of social behavior and argue that understanding neural links between behavior and thermoregulation is timely. First, changes in behavioral states-including social interaction-often accompany changes in body temperature. Second, recent work has uncovered neural populations controlling both thermoregulatory and social behavioral pathways. We identify additional neural populations that, in separate studies, control social behavior and thermoregulation, and highlight their relevance to human and animal studies. Third, dysregulation of body temperature is linked to human neuropsychiatric disorders. Although body temperature is a "hidden state" in many neurobiological studies, it likely plays an underappreciated role in regulating social and affective states.

Glutamatergic neurons in the paraventricular nucleus of the hypothalamus participate in the regulation of visceral pain induced by pancreatic cancer in mice.

Background: Visceral pain induced by pancreatic cancer seriously affects patients' quality of life, and there is no effective treatment, because the mechanism of its neural circuit is unknown. Therefore, the aim of this study is to explore the main neural circuit mechanism regulating visceral pain induced by pancreatic cancer in mice. Methods: The mouse model of pancreatic cancer visceral pain was established on C57BL/6N mice by pancreatic injection of mPAKPC-luc cells. Abdominal mechanical hyperalgesia and hunch score were performed to assess visceral pain; the pseudorabies virus (PRV) was used to identify the brain regions innervating the pancreas; the c-fos co-labeling method was used to ascertain the types of activated neurons; in vitro electrophysiological patch-clamp technique was used to record the electrophysiological activity of specific neurons; the calcium imaging technique was used to determine the calcium activity of specific neurons; specific neuron destruction and chemogenetics methods were used to explore whether specific neurons were involved in visceral pain induced by pancreatic cancer. Results: The PRV injected into the pancreas was detected in the paraventricular nucleus of the hypothalamus (PVN). Immunofluorescence staining showed that the majority of c-fos were co-labeled with glutamatergic neurons in the PVN. In vitro electrophysiological results showed that the firing frequency of glutamatergic neurons in the PVN was increased. The calcium imaging results showed that the calcium activity of glutamatergic neurons in the PVN was enhanced. Both specific destruction of glutamatergic neurons and chemogenetics inhibition of glutamatergic neurons in the PVN alleviated visceral pain induced by pancreatic cancer. Conclusions: Glutamatergic neurons in the PVN participate in the regulation of visceral pain induced by pancreatic cancer in mice, providing new insights for the discovery of effective targets for the treatment of pancreatic cancer visceral pain.

Neuroinflammation in the paraventricular nucleus of the hypothalamus precipitates visceral pain induced by pancreatic cancer in mice.

Background: Given the pivotal role of neuroinflammation in chronic pain and that the paraventricular nucleus of the hypothalamus (PVN) is a crucial brain region involved in visceral pain regulation, we sought to investigate whether the targeted modulation of microglia and astrocytes in the PVN could ameliorate pancreatic cancer-induced visceral pain (PCVP) in mice. Methods: Using a mouse model of PCVP, achieved by tumor cell injection at the head of the pancreas, we measure the number of glial cells, and at the same time we employed minocycline to inhibit microglia and chemogenetic methods to suppress astrocytes in order to investigate the respective roles of microglia and astrocytes within the PVN in PCVP. Results: Mice exhibited visceral pain at 12, 15 and 18 days post-tumor cell injection. We observed a significant increase in the population of both microglia and astrocytes. Inhibition of microglial activity through minocycline microinjection into the PVN resulted in alleviation of visceral pain within 30 and 60 min. Similarly, chemogenetic inhibition of astrocyte function at 14 and 21 days post-injection also led to relief from visceral pain. Conclusions: This study found that PVN microglia and astrocytes were involved in regulating PCVP. Our results suggest that targeting glia may be a potential approach for alleviating visceral pain in patients with pancreatic cancer.

Inhibition of GABAergic neurons in the paraventricular nucleus of the hypothalamus precipitates visceral pain induced by pancreatic cancer in mice.

Background: For patients with pancreatic cancer, visceral pain is a debilitating symptom that significantly compromises their quality of life. Unfortunately, the lack of effective treatment options can be attributed to our limited understanding of the neural circuitry underlying this phenomenon. The primary objective of this study is to elucidate the fundamental mechanisms governing visceral pain induced by pancreatic cancer in murine models. Methods: A mouse model of pancreatic cancer visceral pain was established in C57BL/6N mice through the intrapancreatic injection of mPAKPC-luc cells. Abdominal mechanical hyperalgesia and hunch score were employed to evaluate visceral pain, whereas the in vitro electrophysiological patch-clamp technique was utilized to record the electrophysiological activity of GABAergic neurons. Specific neuron ablation and chemogenetics methods were employed to investigate the involvement of GABAergic neurons in pancreatic cancer-induced visceral pain. Results: In vitro electrophysiological results showed that the firing frequency of GABAergic neurons in the paraventricular nucleus of the hypothalamus (PVN) was decreased. Specific destruction of GABAergic neurons in the PVN exacerbated visceral pain induced by pancreatic cancer. Chemogenetics activation of GABAergic neurons in the PVN alleviated visceral pain induced by pancreatic cancer. Conclusions: GABAergic neurons located in PVN play a crucial role in precipitating visceral pain induced by pancreatic cancer in mice, thereby offering novel insights for identifying effective targets to treat pancreatic cancer-related visceral pain.

Characterization of social hierarchy formation and maintenance in same-sex, group-housed male and female C57BL/6 J mice.

Social hierarchies are a prevalent feature of all animal groups, and an individual's rank within the group can significantly affect their overall health, typically at the greatest expense of the lowest-ranked individuals, or omegas. These subjects have been shown to exhibit various stress-related phenotypes, such as increased hypothalamic-pituitary axis activity and increased amygdalar corticotropin-releasing factor levels compared to higher-ranked subjects. However, these findings have been primarily characterized in males and in models requiring exhibition of severe aggression. The goals of the current study, therefore, were to characterize the formation and maintenance of social hierarchies using the tube test and palatable liquid competition in same-sex groups of male and female C57BL/6 J mice. We also aimed to examine the effects of tube test-determined social rank on plasma and hypothalamic oxytocin and vasopressin levels, peptides with established roles in social behaviors and the stress response. Lastly, we assessed the effects of environmental enrichment and length of testing on the measures outlined above. Overall, we demonstrated that males and females develop social hierarchies and that these hierarchies can be determined using the tube test. While we were unable to establish a consistent connection between peptide levels and social rank, we observed transient changes in these peptides reflecting complex interactions between social rank, sex, environment, and length of testing. We also found that many male and female omegas began to exhibit passive coping behavior after repeated tube test losses, demonstrating the potential of this assay to serve as a model of chronic, mild psychosocial stress.

Neonatal di-(2-ethylhexyl)phthalate exposure induces permanent alterations in secretory CRH neuron characteristics in the hypothalamus paraventricular region of adult male rats.

Corticotrophin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) play a critical role in the modulation of the hypothalamic-pituitary-adrenal (HPA) axis. Early-life exposure to di-(2-ethylhexyl) phthalate (DEHP) has been associated with an increased risk of developing psychiatric disorders in adulthood. The present work was designed to explore the impact of neonatal exposure to DEHP on adult PVN CRH neuronal activity. DEHP or vehicle was given to male rat pups from PND16 to PND22. Then, anxiety-like behaviors, serum corticosterone and testosterone, immunohistochemistry, western blotting, fluorescence in situ hybridization and acute ex vivo slice electrophysiological recordings were used to evaluate the influence of DEHP on adult PVN secretory CRH neurons. Neonatal DEHP-exposed rats exhibited enhanced anxiety-like behaviors in adults, with an increase in CORT. Secretory CRH neurons showed higher spontaneous firing activity but could be inhibited by GABAAR blockers. CRH neurons displayed fewer firing spikes, prolonged first-spike latency, depolarizing shifts in GABA reversal potential and strengthened GABAergic inputs, as indicated by increases in the frequency and amplitude of sIPSCs. Enhancement of GABAergic transmission was accompanied by upregulated expression of GAD67 and downregulated expression of GABABR1, KCC2 and GAT1. These findings suggest that neonatal exposure to DEHP permanently altered the characteristics of secretory CRH neurons in the PVN, which may contribute to the development of psychiatric disorders later in life.

A forebrain-hypothalamic ER stress driven circuit mediates hepatic steatosis during obesity.

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) affects 1 in 3 adults and contributes to advanced liver injury and cardiometabolic disease. While recent evidence points to involvement of the brain in NAFLD, the downstream neural circuits and neuronal molecular mechanisms involved in this response, remain unclear. Here, we investigated the role of a unique forebrain-hypothalamic circuit in NAFLD. METHODS: Chemogenetic activation and inhibition of circumventricular subfornical organ (SFO) neurons that project to the paraventricular nucleus of the hypothalamus (PVN; SFO→PVN) in mice were used to study the role of SFO→PVN signaling in NAFLD. Novel scanning electron microscopy techniques, histological approaches, molecular biology techniques, and viral methodologies were further used to delineate the role of endoplasmic reticulum (ER) stress within this circuit in driving NAFLD. RESULTS: In lean animals, acute chemogenetic activation of SFO→PVN neurons was sufficient to cause hepatic steatosis in a liver sympathetic nerve dependent manner. Conversely, inhibition of this forebrain-hypothalamic circuit rescued obesity-associated NAFLD. Furthermore, dietary NAFLD is associated with marked ER ultrastructural alterations and ER stress in the PVN, which was blunted following reductions in excitatory signaling from the SFO. Finally, selective inhibition of PVN ER stress reduced hepatic steatosis during obesity. CONCLUSIONS: Collectively, these findings characterize a previously unrecognized forebrain-hypothalamic-ER stress circuit that is involved in hepatic steatosis, which may point to future therapeutic strategies for NAFLD.

Oxytocin neurons mediate stress-induced social memory impairment.

Oxytocin has long been thought to play a substantial role in social behaviors, such as social attachment and parenting behavior. However, how oxytocin neurons respond to social and non-social stimuli is largely unknown, especially in high temporal resolution. Here, we recorded the in vivo real-time responses of oxytocin neurons in the paraventricular nucleus of the hypothalamus (PVN) in freely behaving mice. Our results revealed that oxytocin neurons were activated more significantly by stressors than social stimuli. The activation of oxytocin neurons was precisely correlated with struggling behavior during stress. Furthermore, we found that oxytocin mediated stress-induced social memory impairment. Our results reveal an important role of PVN oxytocin neurons in stress-induced social amnesia.

Differential c-Fos Response in Neurocircuits Activated by Repeated Predator Stress in Male and Female C57BL/6J Mice with Stress Sensitive or Resilient Alcohol Intake Phenotypes.

Comorbidity of post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) worsens the prognosis for each of these individual disorders. The current study aimed to identify neurocircuits potentially involved in regulation of PTSD-AUD comorbidity by mapping expression of c-Fos in male and female C57BL/6J mice following repeated predator stress (PS), modeled by exposure to dirty rat bedding. In experiment 1, the levels of c-Fos in the paraventricular nucleus of the hypothalamus (PVH) and the nucleus accumbens shell were higher after the second PS vs the first PS, indicating a sensitized response to this stressor. Additional brain regions showed varied sex-dependent and independent regulation by the two consecutive PS exposures. In experiment 2, mice that increased voluntary alcohol consumption following four exposures to PS (Sensitive subgroup) showed higher c-Fos induction in the PVH, piriform cortex and ventromedial hypothalamus than mice that decreased consumption following these exposures (Resilient subgroup). In contrast to these brain regions, c-Fos was higher in the anterior olfactory nucleus of Resilient vs Sensitive mice. Taken together, these data demonstrate that repeated PS exposure and voluntary alcohol consumption increase neuronal activity across neurocircuits in which specific components depend on the vulnerability of individual mice to these stressors. Increased PVH activity observed across both experiments suggests this brain area as a potential mediator of PS-induced increases in alcohol consumption. Future investigations of specific neuronal populations within the PVH activated by PS, and manipulation of these specific neuronal populations, could improve our understanding of the mechanisms leading to PTSD-AUD comorbidity.

Frequency-coded patterns of sympathetic vasomotor activity are differentially evoked by the paraventricular nucleus of the hypothalamus in the Goldblatt hypertension model.

Introduction: The paraventricular nucleus of the hypothalamus (PVN) contains premotor neurons involved in the control of sympathetic vasomotor activity. It is known that the stimulation of specific areas of the PVN can lead to distinct response patterns at different target territories. The underlying mechanisms, however, are still unclear. Recent evidence from sympathetic nerve recording suggests that relevant information is coded in the power distribution of the signal along the frequency range. In the present study, we addressed the hypothesis that the PVN is capable of organizing specific spectral patterns of sympathetic vasomotor activation to distinct territories in both normal and hypertensive animals. Methods: To test it, we investigated the territorially differential changes in the frequency parameters of the renal and splanchnic sympathetic nerve activity (rSNA and sSNA, respectively), before and after disinhibition of the PVN by bicuculline microinjection. Subjects were control and Goldblatt rats, a sympathetic overactivity-characterized model of neurogenic hypertension (2K1C). Additionally, considering the importance of angiotensin II type 1 receptors (AT1) in the sympathetic responses triggered by bicuculline in the PVN, we also investigated the impact of angiotensin AT1 receptors blockade in the spectral features of the rSNA and sSNA activity. Results: The results revealed that each nerve activity (renal and splanchnic) presents its own electrophysiological pattern of frequency-coded rhythm in each group (control, 2K1C, and 2K1C treated with AT1 antagonist losartan) in basal condition and after bicuculline microinjection, but with no significant differences regarding total power comparison among groups. Additionally, the losartan 2K1C treated group showed no decrease in the hypertensive response triggered by bicuculline when compared to the non-treated 2K1C group. However, their spectral patterns of sympathetic nerve activity were different from the other two groups (control and 2K1C), suggesting that the blockade of AT1 receptors does not totally recover the basal levels of neither the autonomic responses nor the electrophysiological patterns in Goldblatt rats, but act on their spectral frequency distribution. Discussion: The results suggest that the differential responses evoked by the PVN were preferentially coded in frequency, but not in the global power of the vasomotor sympathetic responses, indicating that the PVN is able to independently control the frequency and the power of sympathetic discharges to different territories.

Plasticity in parental behavior and vasopressin: responses to co-parenting, pup age, and an acute stressor are experience-dependent.

Introduction: The impact of variation in parental caregiving has lasting implications for the development of offspring. However, the ways in which parents impact each other in the context of caregiving is comparatively less understood, but can account for much of the variation observed in the postnatal environment. Prairie voles (Microtus ochrogaster) demonstrate a range of postnatal social groups, including pups raised by biparental pairs and by their mothers alone. In addition to the challenges of providing parental care, prairie vole parents often experience acute natural stressors (e.g., predation, foraging demands, and thermoregulation) that could alter the way co-parents interact. Methods: We investigated how variation in the experience of raising offspring impacts parental behavior and neurobiology by administering an acute handling stressor on prairie vole families of single mothers and biparental parents over the course of offspring postnatal development. Results: Mothers and fathers exhibited robust behavioral plasticity in response to the age of their pups, but in sex-dependent ways. Pup-directed care from mothers did not vary as a function of their partner's presence, but did covary with the number of hypothalamic vasopressin neurons in experience-dependent ways. The relationship between vasopressin neuron numbers and fathers' behaviors was also contingent upon the stress handling manipulation, suggesting that brain-behavior associations exhibit stress-induced plasticity. Conclusion: These results demonstrate that the behavioral and neuroendocrine profiles of adults are sensitive to distinct and interacting experiences as a parent, and extend our knowledge of the neural mechanisms that may facilitate parental behavioral plasticity.

A neural circuit for gastric motility disorders driven by gastric dilation in mice.

Introduction: Symptoms of gastric motility disorders are common clinical manifestations of functional gastrointestinal disorders (FGIDs), and are triggered and exacerbated by stress, but the neural pathways underpinning them remain unclear. Methods: We set-up a mouse model by gastric dilation (GD) in which the gastric dynamics were assessed by installing strain gauges on the surface of the stomach. The neural pathway associated with gastric motility disorders was investigated by behavioral tests, electrophysiology, neural circuit tracing, and optogenetics and chemogenetics involving projections of the corticotropin-releasing hormone (CRH) from the paraventricular nucleus of the hypothalamus (PVN) to acetylcholine (ChAT) neurons in the dorsal motor nucleus of the vagus (DMV). Results: We found that GD induced gastric motility disorders were accompanied by activation of PVN CRH neurons, which could be alleviated by strategies that inhibits the activity of PVN CRH neurons. In addition, we identified a neural pathway in which PVN CRH neurons project into DMV ChAT neurons, modulated activity of the PVN CRH →DMV ChAT pathway to alleviate gastric motility disorders induced by GD. Discussion: These findings indicate that the PVN CRH →DMV ChAT pathway may mediate at least some aspects of GD related gastric motility, and provide new insights into the mechanisms by which somatic stimulation modulates the physiological functions of internal organs and systems.

The intersection of empathy and addiction.

Empathy, the ability to perceive the affective state of another, is a complex process that is integral to many of the prosocial behaviors expressed in humans and across the animal kingdom. Research into the behavioral and neurobiological underpinnings of empathic behaviors has increased in recent years. Growing evidence suggests changes in empathy may contribute to a myriad of psychiatric illnesses, including substance use disorder (SUD). Indeed, both clinical and preclinical research in SUD demonstrates a strong relationship between drug taking or relapse events and changes to empathic behavior. Further, there is significant overlap in the underlying neural substrates of these complex behaviors, including the insula, paraventricular nucleus of thalamus (PVT), and the paraventricular nucleus of the hypothalamus (PVN). In this review, we will discuss our current understanding of the interplay between empathic behaviors and SUD. We will also examine the underlying neurobiology that may regulate this interaction, focusing specifically on the insula, PVT, and PVN. Finally, we discuss the biologic and therapeutic importance of taking empathic processes into consideration when discussing SUD.

Alterations in the activation of corticotropin-releasing factor neurons in the paraventricular nucleus following a single or multiple days of sleep restriction.

Sleep disturbances are common among disorders associated with hypothalamic pituitary-adrenal (HPA) axis dysfunction, such as depression and anxiety. This comorbidity may partly be the result of the intersection between the role of the HPA axis in mediating the stress response and its involvement in sleep-wake cyclicity. Our previous work has shown that following 20 h of sleep restriction, mice show a blunting of the HPA axis in response to an acute stressor. Furthermore, these responses differ in a sex-dependent manner. This study sought to examine the effect of sleep restriction on corticotropin-releasing factor (CRF)-containing neurons in the paraventricular nucleus (PVN) of the hypothalamus. Male and female Crf-IRES-Cre: Ai14 (Tdtomato) reporter mice were sleep restricted for 20 h daily for either a single or three consecutive days using the modified multiple platform method. These mice allowed the visualization of CRF+ neurons throughout the brain. Animals were subjected to acute restraint stress, and their brains were collected to assess PVN neuronal activation via c-Fos immunohistochemistry. Analyses of cell counts revealed an ablation of the restraint-induced increase in both CRF/c-Fos colocalization and overall c-Fos expression in female mice following both a single day and three days of sleep restriction. Males showed an overall decrease in restraint-induced c-Fos levels following a single day of sleep restriction. However, male mice examined after three days of sleep restriction showed a recovery in PVN-CRF and overall PVN neuronal activation. These data suggest the sex dependent dysregulation in CRF function following sleep restriction.

Chronic high-fat diet induces overeating and impairs synaptic transmission in feeding-related brain regions.

Obesity is linked to overeating, which can exacerbate unhealthy weight gain. However, the mechanisms for mediating such linkages are elusive. In the current study, we hypothesized that synaptic remodeling occurs in feeding-related brain regions of obese mice. To investigate this, we established a high-fat diet (HFD)-induced obese mouse model and observed that these mice consumed excessive calories. The effect of chronic HFD feeding on lipid droplet accumulation in different brain structures was also investigated. We found that lipid droplets accumulated on the ependyma of the third ventricle (3V), which is surrounded by key areas of the hypothalamus that are involved in feeding. Then, the spontaneous synaptic activity of miniature excitatory postsynaptic current (mEPSC) and miniature inhibitory postsynaptic current (mIPSC) was recorded in these hypothalamic areas. HFD induced a decreased amplitude of mEPSC in the arcuate nucleus (ARC) and the ventromedial hypothalamus (VMH), meanwhile, increased the frequency in the VMH. In addition, HFD reduced the frequency of mIPSC in the lateral hypothalamus (LH) and increased the amplitude of mIPSC in the paraventricular nucleus of the hypothalamus (PVH). Subsequently, we also measured the synaptic activity of nucleus accumbens (NAc) neurons, which play a vital role in the hedonic aspect of eating, and discovered that HFD diminished the frequency of both mEPSC and mIPSC in the NAc. These findings suggest that chronic HFD feeding leads to lipid accumulation and synaptic dysfunction in specific brain regions, which are associated with energy homeostasis and reward regulation, and these impairments may lead to the overeating of obesity.

Adenosine Downregulates the Activities of Glutamatergic Neurons in the Paraventricular Hypothalamic Nucleus Required for Sleep.

Adenosine is an endogenous substance that regulates sleep homeostasis. It plays an important role in sleep induction under physiological condition. So far, the neural mechanisms underlying sleep-promoting effects of adenosine are not completely clear. Recent studies have shown that glutamatergic neurons in the paraventricular hypothalamic nucleus (PVH) play an important role in wakefulness. Using whole-cell patch-clamp, we found that adenosine can inhibit glutamatergic neurons in PVH. This inhibition is mainly achieved by activating adenosine type 1 receptors, thereby reducing hyperpolarization-activated cyclic nucleotide-gated cation channels. By recording electroencephalogram (EEG) and electromyography (EMG), it was found that local administration of adenosine type 1 receptor blocker in PVH could significantly reduce the NREM sleep. On the contrary, if adenosine was given, it could increase the NREM sleep. These results suggest that adenosine can promote sleep by reducing the excitability of PVH neurons. This findings reveal a novel mechanism of adenosine regulating sleep homeostasis.

ACE2, Circumventricular Organs and the Hypothalamus, and COVID-19.

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.

Berbamine reduces body weight via suppression of small GTPase Rab8a activity and activation of paraventricular hypothalamic neurons in obese mice.

Small GTPase Rab8a is involved in fat-specific protein 27 (Fsp27) mediated lipid droplet accumulation in adipocytes. By screening inhibitors of Rab8a GTPase from a natural compound library, berbamine (BBM), a marketing drug for treatment of leukopenia in China, was identified to inhibit the activity of Rab8a GTPase and block the differentiation of 3T3-L1 adipocytes. Animal study showed that BBM could reduce body weight, improved glucose and lipid metabolic homeostasis in high-fat diet-induced obesity (DIO) C57BL/6 mice and db/db mice. Additional, BBM increased energy expenditure and inhibited food intake in mice but not in lean mice. Moreover, intracerebroventricular injection (i.c.v.) of BBM inhibited feeding behavior and increased c-Fos expression in paraventricular nucleus of the hypothalamus (PVH) of mice. Our data suggest that BBM may improve obesity through the inhibition of Rab8a GTPase activity and the activation of anorexigenic energy-sensing neuron in PVH.

Relative Contribution of Blood Pressure and Renal Sympathetic Nerve Activity to Proximal Tubular Sodium Reabsorption via NHE3 Activity.

We examined the effects of an acute increase in blood pressure (BP) and renal sympathetic nerve activity (rSNA) induced by bicuculline (Bic) injection in the paraventricular nucleus of hypothalamus (PVN) or the effects of a selective increase in rSNA induced by renal nerve stimulation (RNS) on the renal excretion of sodium and water and its effect on sodium-hydrogen exchanger 3 (NHE3) activity. Uninephrectomized anesthetized male Wistar rats were divided into three groups: (1) Sham; (2) Bic PVN: (3) RNS + Bic injection into the PVN. BP and rSNA were recorded, and urine was collected prior and after the interventions in all groups. RNS decreased sodium (58%) and water excretion (53%) independently of BP changes (p < 0.05). However, after Bic injection in the PVN during RNS stimulation, the BP and rSNA increased by 30% and 60% (p < 0.05), respectively, diuresis (5-fold) and natriuresis (2.3-fold) were increased (p < 0.05), and NHE3 activity was significantly reduced, independently of glomerular filtration rate changes. Thus, an acute increase in the BP overcomes RNS, leading to diuresis, natriuresis, and NHE3 activity inhibition.

Vasopressin and Breathing: Review of Evidence for Respiratory Effects of the Antidiuretic Hormone.

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.