Medial Preoptic Area Research Articles

Hormonal actions in the medial preoptic area governing parental behaviour: Novel insights from new tools.

The importance of hormones in mediating a behavioural transition in mammals from a virgin or non-parenting state to parental state was established around 50 years ago. Extensive research has since revealed a highly conserved neural circuit that underlies parental behaviour both between sexes and between mammalian species. Within this circuit, hormonal action in the medial preoptic area of the hypothalamus (MPOA) has been shown to be key in timing the onset of parental behaviour with the birth of offspring. However, the mechanism underlying how hormones act in the MPOA to facilitate this change in behaviour has been unclear. Technical advances in neuroscience, including single cell sequencing, novel transgenic approaches, calcium imaging, and optogenetics, have recently been harnessed to reveal new insights into maternal behaviour. This review aims to highlight how the use of these tools has shaped our understanding about which aspects of maternal behaviour are regulated by specific hormone activity within the MPOA, how hormone-sensitive MPOA neurons integrate within the wider neural circuit that governs maternal behaviour, and how maternal hormones drive changes in MPOA neuronal function during different reproductive states. Finally, we review our current understanding of hormonal modulation of MPOA-mediated paternal behaviour in males.

Paternal behaviour is associated with high levels of OT in plasma and the presence OTR in the mPOA/BNST in the Mongolian gerbil (Meriones unguiculatus)

The exhibition of paternal behaviour has been associated with high peripheral concentrations of oxytocin (OT) and levels of oxytocin receptors (OTRs) in the paraventricular and supraoptic nuclei of the hypothalamus. The presence of OTRs in the medial preoptic area (mPOA), bed nucleus of the stria terminalis (BNST), medial amygdala (MeA), and olfactory bulb (OB) has not been studied extensively in the paternal context, although these nuclei are essential in the regulation of paternal behaviour. The aim of this study was to determine whether there is an association between paternal response of sexually inexperienced males of the Mongolian gerbils (Meriones unguiculatus) and OT concentrations in plasma, as well as the presence of OTRs in the mPOA, BNST, MeA, and OB. We used sexually inexperienced gerbils: ten paternal (PAT) males and 10 males aggressive with pups (AGG). PAT males and AGG males were subjected to paternal behaviour tests. Then, blood samples were taken to quantify OT concentrations. The brains were dissected for OTR immunohistochemistry analyses. PAT males had significantly higher plasma levels of OT and numbers of cells with OTR immunoreactivity (ir) in the mPOA/BNST. These results indicated an association between paternal behaviour and peripheral concentrations of OT, as well as the presence of OTRs in the mPOA and BNST. This suggests that OT and OTRs could participate in the regulation of paternal behaviour in the Mongolian gerbil.

The Orexin OX2 Receptor-Dependent Pathway Is Implicated in the Development of Overactive Bladder and Depression in Rats Exposed to Corticosterone.

In the present study, we wanted to check whether TCS OX2 29 (TCS), a potent selective antagonist of OX2 receptors, would have positive effects in an animal model of detrusor overactivity co-existed with the depression-like state in Wistar male rats. The forced swim test with the measurement of spontaneous locomotor activity, conscious cystometry, determination of c-Fos expression in central micturition areas, and a set of biochemical analyses (with the use of urine, hippocampus, bladder urothelium, and detrusor muscle of tested animals) were carried out. The outcomes showed that a 7-day administration of TCS (3 mg/kg/day, subcutaneously) normalizes the cystometric parameters corresponding to overactivity of the detrusor and reverses the pro-depressive response. Furthermore, the antagonism of OX2 receptors restored the abnormal levels of overactive bladder markers (i.e., ATP, CGRP, OCT3, TRPV1, ROCK1, and VAChT), diminished neuronal overactivity in central micturition areas (i.e., pontine micturition center, ventrolateral periaqueductal gray, and medial preoptic area) as well as restored the altered hippocampal levels of CRF, cytokines (IL-1β, IL-6, IL-10, and TNF-α), and growth factors (BDNF and NGF) that reflected biochemical disturbances detected in depressed people. It seems that our findings open new perspectives regarding the implication of the orexin system in the functioning of the urinary bladder and in the pathophysiology of depression.

7996 Neuroanatomic Characterization of Mouse Kisspeptin Neurons in the Bed Nucleus of the Stria Terminalis

Abstract Disclosure: S.T. Zdon: None. M.S. Silva: None. V.M. Navarro: None. Kisspeptin (Kiss1) neurons are essential for reproductive function as they are strong regulators of the hypothalamic-pituitary-gonadal axis (HPG). Mammalian Kiss1 neurons are mainly located in the hypothalamus, controlling gonadotropin-releasing hormone (GnRH) secretion, where the anteroventral periventricular nucleus (AVPV) population is morphologically and functionally sexually differentiated. Kiss1 neurons are also found in limbic areas, such as the bed nucleus of the stria terminalis (BNST). This nucleus is involved in the integration of the HPG axis with sex-dependent social behaviors and metabolic functions. However, it remains unclear whether these populations show sexually dimorphic features. The present study focused on the neuroanatomical characterization of Kiss1BNST neurons in mice on both sexes. A Kiss1cre;salsa6f mouse strain carrying the expression of tdTomato specifically in Kiss1 neurons was used to study the distribution of Kiss1BNST neurons. The BNST is divided into the anterior division of the BNST (aBNST), and a more posterior division called the principal component of the BNST (prBNST). Results indicate that male mice have significantly more Kiss1prBNST neurons than females (Male: 139.4 ± 23.32 vs. Female: 43.70 ± 5.33 neurons; **P < 0.01). This sex-biased distribution was absent in Kiss1aBNST neurons. Additionally, stereotaxically injecting a Cre-dependent recombinant adenovirus carrying the expression of mCherry reporter into the aBNST or prBNST in adult mice was performed to observe neuronal projections. We observed fibers from aBNST-injected Kiss1 neurons projecting widely to areas that include the AVPV, medial preoptic area (MPO), lateral preoptic area (LPO), and periventricular hypothalamic nucleus (PVH). Moreover, fibers and cell bodies from male prBNST-injected Kiss1 neurons projected to dorsal lateral BNST (dlBNST), juxta-periventricular lateral hypothalamic area (JPLH), and the posterolateral stria terminalis (STMPL). This study observed a sexual dimorphic Kiss1 neuronal population in the prBNST, with males having more Kiss1prBNST neurons present and prospective postsynaptic areas in the brain where these neurons project to, helping to aid future studies on characterizing the functional role of these neurons. Presentation: 6/1/2024

Excitation-inhibition imbalance in medial preoptic area circuits underlies chronic stress-induced depression-like states

Dysregulation of brain homeostasis is associated with neuropsychiatric conditions such as major depressive disorder. However, underlying neural-circuit mechanisms remain not well-understood. We show in mice that chronic restraint stress (CRS) and social defeat stress (SDS) are both associated with disruption of excitation (E)-inhibition (I) balance, with increased E/I ratios, in medial preoptic area (MPOA) circuits, but through affecting different neuronal types. CRS results in elevated activity in glutamatergic neurons, and their suppression mitigates CRS-induced depressive-like behaviors. Paraventricular hypothalamic input to these neurons contributes to induction but not expression of depressive-like behaviors. Their projections to ventral tegmental area and periaqueductal gray/dorsal raphe suppress midbrain dopaminergic and serotonergic activity, respectively, and mediate expression of divergent depressive-like symptoms. By contrast, SDS results in reduced activity of GABAergic neurons, and their activation alleviates SDS-induced depressive-like behaviors. Thus, E/I imbalance with relatively increased excitation in MPOA circuits may be a general mechanism underlying depression caused by different etiological factors.

Effects of prenatal cocaine exposure on estrous cycle, and behavior and expression of estrogen receptor alpha and oxytocin during estrus and diestrus in mice offspring.

Increasing evidence indicates that prenatal cocaine exposure may result in many developmental and long-lasting neurological and behavioral effects. The behaviors of female animals are strongly associated with the estrous cycle. Estrogen receptors and oxytocin are important neuroendocrine factors that regulate social behavior and are of special relevance to females. However, whether prenatal cocaine exposure induces estrous cycle changes in offspring and whether neurobehavioral changes in estrus and diestrus offspring differ remains unclear. On gestational day 12, mice were administered cocaine once daily for seven consecutive days, then the estrous cycle was examined in adult female offspring, as well as locomotion, anxiety level, and social behaviors, and the expression of estrogen receptor alpha-immunoreactive and oxytocin-immunoreactive neurons were compared between estrus and diestrus offspring. Prenatal cocaine exposure resulted in the shortening of proestrus and estrus in the offspring. During estrus and diestrus, prenatally cocaine-exposed offspring showed increased anxiety levels and changed partial social behaviors; their motility showed no significant differences in estrus, but declined in diestrus. Prenatal cocaine exposure reduced estrogen receptor alpha-immunoreactive expression in the medial preoptic area, ventromedial hypothalamic nucleus, and arcuate nucleus and oxytocin-immunoreactive expression in the paraventricular nucleus in estrus and diestrus offspring. These results suggest that prenatal cocaine exposure induces changes in the offspring's estrous cycle and expression of estrogen receptor alpha and oxytocin in a brain region-specific manner and that prenatal cocaine exposure and the estrous cycle interactively change motility and partial social behavior. Estrogen receptor alpha and oxytocin signaling are likely to play important concerted roles in mediating the effects of prenatal cocaine exposure on the offspring.

A Theory on the Nonlinear Relationship of Sexual Behavior and Aggression

Objective: Claims have been made that more sexual liberalism in society than what generally existed in human history is necessary to promote societal tranquility and reduce violence. This research was conducted to investigate the real relationship between sexual behavior and aggression based on scientific data especially from the perspective of physiological psychology. Method: This study was a narrative review and utilized evidence-based findings from neuropsychology, psychophysiology, laboratory research, and field studies. Databases were explored for related terms until sufficiency was reached. The findings were categorized and analyzed descriptively and interpretively to establish connections between the findings. Ultimately, a comprehensive conceptualization was developed to conclude a theory on the relationship between sexual behavior, sexual satiety, and aggression. Results: The study indicated that unrestrained sexual behavior leads to an escalation of the behavior, rather than satiation, and aggression rather than calmness. This may be due to positive feedback in the nervous and hormonal systems, specifically mediated by the medial preoptic area (MPA) and testosterone, leading to aggressive behavior. However, since sexual deprivation can potentially lead to aggression, it is advisable to view the relationship between sexual activity and violence as a non-linear one. Conclusion: This paper establishes that the intensification of sexual behaviors leads to increased violence and aggression in society, ultimately elevating levels of public insecurity. Therefore, limiting sexual behavior within the framework of the relationship of married couples may serve as a moderating factor for this phenomenon.

Opposing actions of co-released GABA and neurotensin on the activity of preoptic neurons and on body temperature.

Neurotensin (Nts) is a neuropeptide acting as a neuromodulator in the brain. Pharmacological studies have identified Nts as a potent hypothermic agent. The medial preoptic area, a region that plays an important role in the control of thermoregulation, contains a high density of neurotensinergic neurons and Nts receptors. The conditions in which neurotensinergic neurons play a role in thermoregulation are not known. In this study, optogenetic stimulation of preoptic Nts neurons induced a small hyperthermia. In vitro, optogenetic stimulation of preoptic Nts neurons resulted in synaptic release of GABA and net inhibition of the preoptic pituitary adenylate cyclase-activating polypeptide (Adcyap1) neurons firing activity. GABA-A receptor antagonist or genetic deletion of Slc32a1 (VGAT) in Nts neurons unmasked also an excitatory effect that was blocked by a Nts receptor 1 antagonist. Stimulation of preoptic Nts neurons lacking Slc32a1 resulted in excitation of Adcyap1 neurons and hypothermia. Mice lacking Slc32a1 expression in Nts neurons presented changes in the fever response and in the responses to heat or cold exposure as well as an altered circadian rhythm of body temperature. Chemogenetic activation of all Nts neurons in the brain induced a 4-5°C hypothermia, which could be blocked by Nts receptor antagonists in the preoptic area. Chemogenetic activation of preoptic neurotensinergic projections resulted in robust excitation of preoptic Adcyap1 neurons. Taken together, our data demonstrate that endogenously released Nts can induce potent hypothermia and that excitation of preoptic Adcyap1 neurons is the cellular mechanism that triggers this response.

Poweromin X Ten, a polyherbal formulation improves male sexual function: In vivo and network pharmacology study.

Poweromin X Ten (PXT) is a polyherbal formulation, traditionally used to enhance male sexual function. However, the safety and benefits of PXT have not been scientifically evaluated. Therefore, the present study investigated the toxicity and aphrodisiac potential of PXT in male rats and explored its principal mechanisms of action. Male Wistar rats were orally administered PXT (50 or 100 mg/kg) for 28 days, and sexual activity parameters, including latency and frequency of mounting and intromissions, were studied. The reproductive toxicity and spermatogenic potential were also examined. Furthermore, dopamine and serotonin levels in brain regions associated with sexual activity were assessed. Network analysis was used to identify the key bioactive compounds and their core targets involved in their beneficial actions. Treatment with PXT improved sexual activity in male rats, as evidenced by reduced mounting and intromission latency and a significant increase in mount frequency. Moreover, PXT exhibited spermatogenic potential and did not induce reproductive toxicity. Notably, treatment with 50 mg/kg PXT elevated dopamine levels in median preoptic area and hypothalamus. Pathway analysis indicated that PXT primarily modulated the PI3K-Akt, calcium, and MAPK signalling pathways to enhance male sexual function. Network analysis identified macelignan, β-estradiol, testosterone, and paniculatine as key bioactive components of PXT, which likely act through core targets, such as androgen receptor (AR), Mitogen-activated protein kinase 3 (MAPK3), epidermal growth factor receptor (EGFR), estrogen receptor 1 (ESR1), and vascular endothelial growth factor (VEGF) to facilitate the improvement of male sexual function. Study results suggest that PXT is a safer alternative with aphrodisiac and spermatogenic potential. These effects are partly attributed to the enhanced dopamine levels in the brain. Furthermore, this study provides insights into the specific signalling pathways and bioactive compounds that underlie the improvements in male sexual function associated with PXT.

Cellular evolution of the hypothalamic preoptic area of behaviorally divergent deer mice.

Genetic variation is known to contribute to the variation of animal social behavior, but the molecular mechanisms that lead to behavioral differences are still not fully understood. Here, we investigate the cellular evolution of the hypothalamic medial preoptic area (MPOA), a brain region that plays a critical role in social behavior, across two sister species of deer mice (Peromyscus maniculatus and P. polionotus) with divergent social systems. These two species exhibit large differences in mating and parental care behavior across species and sex. Using single-nucleus RNA-sequencing, we build a cellular atlas of the MPOA for males and females of both Peromyscus species. We identify four cell types that are differentially abundant across species, two of which may account for species differences in parental care behavior. Our data further implicate two sex-biased cell types to be important for the evolution of sex-specific behavior. Finally, we show a remarkable reduction of sex-biased gene expression in P. polionotus, a monogamous species that also exhibits reduced sexual dimorphism in parental care behavior. Our MPOA atlas is a powerful resource to investigate how molecular neuronal traits may be evolving to give rise to innate differences in social behavior across animal species.

RNA-sequencing reveals a shared neurotranscriptomic profile in the medial preoptic area of highly social songbirds and rats.

Rough-and-tumble play in juvenile rats and song in flocks of adult songbirds outside a breeding context (gregarious song) are two distinct forms of non-sexual social behavior. Both are believed to play roles in the development of sociomotor skills needed for later life-history events, including reproduction, providing opportunities for low-stakes practice. Additionally, both behaviors are thought to be intrinsically rewarded and are associated with a positive affective state. Given the functional similarities of these behaviors, this study used RNA-sequencing to identify commonalities in their underlying neurochemical systems within the medial preoptic area. This brain region is implicated in multiple social behaviors, including song and play, and is highly conserved across vertebrates. DESeq2 and rank-rank hypergeometric overlap analyses identified a shared neurotranscriptomic profile in adult European starlings singing high rates of gregarious song and juvenile rats playing at high rates. Transcript levels for several glutamatergic receptor genes, such as GRIN1, GRIN2A, and GRIA1, were consistently upregulated in highly gregarious (i.e., playful/high singing) animals. This study is the first to directly investigate shared neuromodulators of positive, non-sexual social behaviors across songbirds and mammals. It provides insight into a conserved brain region that may regulate similar behaviors across vertebrates.

A Hypothalamic Circuit that Modulates Feeding and Parenting Behaviors.

Across mammalian species, new mothers undergo considerable behavioral changes to nurture their offspring and meet the caloric demands of milk production1-5. While many neural circuits underlying feeding and parenting behaviors are well characterized6-9, it is unclear how these different circuits interact and adapt during lactation. Here, we characterized the transcriptomic changes in the arcuate nucleus (ARC) and the medial preoptic area (MPOA) of the mouse hypothalamus in response to lactation and hunger. Furthermore, we showed that heightened appetite in lactating mice was accompanied by increased activity of hunger-promoting agouti-related peptide (AgRP) neurons in the ARC. To assess the strength of hunger versus maternal drives, we designed a conflict assay where female mice chose between a food source or a chamber containing pups and nesting material. Although food-deprived lactating mothers prioritized parenting over feeding, hunger reduced the duration and disrupted the sequences of parenting behaviors in both lactating and virgin females. We discovered that ARCAgRP neurons directly inhibit bombesin receptor subtype-3 (BRS3) neurons in the MPOA, a population that governs both parenting and satiety. Selective activation of this ARCAgRP to MPOABRS3 circuit shifted behaviors from parenting to food-seeking. Thus, hypothalamic networks are modulated by physiological states and work antagonistically during the prioritization of competing motivated behaviors.

Effects of acute inhibition of dopamine β-hydroxylase on neural responses to pups in adult virgin male California mice (Peromyscus californicus)

The neural mechanisms underlying paternal care in biparental mammals are not well understood. The California mouse (Peromyscus californicus) is a biparental rodent in which virtually all fathers are attracted to pups, while virgin males vary widely in their behavior toward unrelated infants, ranging from attacking to avoiding to huddling and grooming pups. We previously showed that pharmacologically inhibiting the synthesis of the neurotransmitter norepinephrine (NE) with the dopamine β-hydroxylase inhibitor nepicastat reduced the propensity of virgin male and female California mice to interact with pups. The current study tested the hypothesis that nepicastat would reduce pup-induced c-Fos immunoreactivity, a cellular marker of neural activity, in the medial preoptic area (MPOA), medial amygdala (MeA), basolateral amygdala (BLA), and bed nucleus of the stria terminalis (BNST), brain regions implicated in the control of parental behavior and/or anxiety. Virgin males were injected with nepicastat (75 mg/kg, i.p.) or vehicle 2 hours prior to exposure to either an unrelated pup or novel object for 60 minutes (n = 4–6 mice per group). Immediately following the 60-minute stimulus exposure, mice were euthanized and their brains were collected for c-Fos immunohistochemistry. Nepicastat reduced c-Fos expression in the MeA and MPOA of pup-exposed virgin males compared to vehicle-injected controls. In contrast, nepicastat did not alter c-Fos expression in any of the above brain regions following exposure to a novel object. Overall, these results suggest that the noradrenergic system might influence MeA and MPOA function to promote behavioral interactions with pups in virgin males.

Is paracetamol a neuroendocrine disruptor of the developing sexual brain?

Although paracetamol is considered a safe medication during pregnancy at therapeutic doses, and despite animal studies showing no negative effects or reporting no adverse effects during pregnancy, there are no well-controlled clinical studies demonstrating the safety for both the mother and fetus. Therefore, its use in this situation depends on the physician’s discretion. Its mechanism involves the inhibition of the enzymes cyclooxygenase 2 and 3 (COX-2,3), which modulate pain and inflammation by reducing prostaglandins. However, COX-2 and prostaglandins are also part of the molecular cascade organizing the brain towards a male direction during the prenatal period, and potentially during other periods as well. Herein, we hypothesize that paracetamol, a common medication used to treat fever and pain, may have long-term effects as a neuroendocrine disruptor of the sexual brain when administered during critical periods of development such as pregnancy, and to a lesser extent, during the neonatal, infancy, and puberty periods. Throughout this manuscript, we discuss the effects of COX-2,3 inhibition on the organization of the brain and sexual partner preference, particularly affecting masculinization of the medial preoptic area. We argue how administration of paracetamol in critical periods of plasticity might have an enduring effect on sexual behavior and other motivated behaviors. Impairments in each of these processes can directly impact individuals’ sexual and mental health. We also discuss how sexual experience in adulthood ameliorated the impaired sexual preference of paracetamol-treated males, indicating an interaction between biological and environmental mechanisms. This manuscript is meant to warn professionals that although paracetamol is a very effective and safe drug, it is likely to disorganize the developing sexual brain, probably contributing to what we call iatrogenic sexual diversity.

Shared and unique transcriptomic signatures of antidepressant and probiotics action in the mammalian brain.

Understanding the shared and divergent mechanisms across antidepressant (AD) classes and probiotics is critical for improving treatment for mood disorders. Here we examine the transcriptomic effects of bupropion (NDRI), desipramine (SNRI), fluoxetine (SSRI) and a probiotic formulation (Lacidofil®) on 10 regions across the mammalian brain. These treatments massively alter gene expression (on average, 2211 differentially expressed genes (DEGs) per region-treatment combination), highlighting the biological complexity of AD and probiotic action. Intersection of DEG sets against neuropsychiatric GWAS loci, sex-specific transcriptomic portraits of major depressive disorder (MDD), and mouse models of stress and depression reveals significant similarities and differences across treatments. Interestingly, molecular responses in the infralimbic cortex, basolateral amygdala and locus coeruleus are region-specific and highly similar across treatments, whilst responses in the Raphe, medial preoptic area, cingulate cortex, prelimbic cortex and ventral dentate gyrus are predominantly treatment-specific. Mechanistically, ADs concordantly downregulate immune pathways in the amygdala and ventral dentate gyrus. In contrast, protein synthesis, metabolism and synaptic signaling pathways are axes of variability among treatments. We use spatial transcriptomics to further delineate layer-specific molecular pathways and DEGs within the prefrontal cortex. Our study reveals complex AD and probiotics action on the mammalian brain and identifies treatment-specific cellular processes and gene targets associated with mood disorders.

Re-wiring of the bonded brain: Gene expression among pair bonded female prairie voles changes as they transition to motherhood.

Motherhood is a costly life-history transition accompanied by behavioral and neural plasticity necessary for offspring care. Motherhood in the monogamous prairie vole is associated with decreased pair bond strength, suggesting a trade-off between parental investment and pair bond maintenance. Neural mechanisms governing pair bonds and maternal bonds overlap, creating possible competition between the two. We measured mRNA expression of genes encoding receptors for oxytocin (oxtr), dopamine (d1r and d2r), mu-opioids (oprm1a), and kappa-opioids (oprk1a) within three brain areas processing salience of sociosensory cues (anterior cingulate cortex; ACC), pair bonding (nucleus accumbens; NAc), and maternal care (medial preoptic area; MPOA). We compared gene expression differences between pair bonded prairie voles that were never pregnant, pregnant (~day 16 of pregnancy), and recent mothers (day 3 of lactation). We found greater gene expression in the NAc (oxtr, d2r, oprm1a, and oprk1a) and MPOA (oxtr, d1r, d2r, oprm1a, and oprk1a) following the transition to motherhood. Expression for all five genes in the ACC was greatest for females that had been bonded for longer. Gene expression within each region was highly correlated, indicating that oxytocin, dopamine, and opioids comprise a complimentary gene network for social signaling. ACC-NAc gene expression correlations indicated that being a mother (oxtr and d1r) or maintaining long-term pair bonds (oprm1a) relies on the coordination of different signaling systems within the same circuit. Our study suggests the maternal brain undergoes changes that prepare females to face the trade-off associated with increased emotional investment in offspring, while also maintaining a pair bond.

Thermoregulatory pathway underlying the pyrogenic effects of prostaglandin E2 in the lateral parabrachial nucleus of male rats.

It has been shown that prostaglandin (PG) E2 synthesized in the lateral parabrachial nucleus (LPBN) is involved in lipopolysaccharide-induced fever. But the neural mechanisms of how intra-LPBN PGE2 induces fever remain unclear. In this study, we investigated whether the LPBN-preoptic area (POA) pathway, the thermoafferent pathway for feed-forward thermoregulatory responses, mediates fever induced by intra-LPBN PGE2 in male rats. The core temperature (Tcore) was monitored using a temperature radiotelemetry transponder implanted in rat abdomen. We showed that microinjection of PGE2 (0.28 nmol) into the LPBN significantly enhanced the density of c-Fos-positive neurons in the median preoptic area (MnPO). The chemical lesioning of MnPO with ibotenate or selective genetic lesioning or inhibition of the LPBN-MnPO pathway significantly attenuated fever induced by intra-LPBN injection of PGE2. We demonstrated that EP3 receptor was a pivotal receptor for PGE2-induced fever, since microinjection of EP3 receptor agonist sulprostone (0.2 nmol) or EP3 receptor antagonist L-798106 (2 nmol) into the LPBN mimicked or weakened the pyrogenic action of LPBN PGE2, respectively, but this was not the case for EP4 and EP1 receptors. Whole-cell recording from acute LPBN slices revealed that the majority of MnPO-projecting neurons originating from the external lateral (el) and dorsal (d) LPBN were excited and inhibited, respectively, by PGE2 perfusion, initiating heat-gain and heat-loss mechanisms. The amplitude but not the frequency of spontaneous and miniature glutamatergic excitatory postsynaptic currents (sEPSCs and mEPSCs) in MnPO-projecting LPBel neurons increased after perfusion with PGE2; whereas the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) and the A-type potassium (IA) current density did not change. In MnPO-projecting LPBd neurons, neither sEPSCs nor sIPSCs responded to PGE2; however, the IA current density was significantly increased by PGE2 perfusion. These electrophysiological responses and the thermoeffector reactions to intra-LPBN PGE2 injection, including increased brown adipose tissue thermogenesis, shivering, and decreased heat dissipation, were all abolished by L-798106, and mimicked by sulprostone. These results suggest that the pyrogenic effects of intra-LPBN PGE2 are mediated by both the inhibition of the LPBd-POA pathway through the EP3 receptor-mediated activation of IA currents and the activation of the LPBel-POA pathway through the selective enhancement of glutamatergic synaptic transmission via EP3 receptors.

Estrogenic re-mapping of the metabolic response to an energy deficit

Endothermy is an adaptation that can be traced back hundreds of millions of years and is critical for nearly every aspect of mammalian biology. Despite the advantages associated with a stable internal temperature, endothermy is energetically expensive. To conserve energy when food is scarce, mice have evolved the ability to reversibly enter a regulated state of hypothermia and hypometabolism, known as torpor. We have found that circulating 17β-estradiol, a potent estrogen, inhibits fasting-induced torpor in ovariectomized female mice, yet the signaling mechanisms underlying this estrogenic re-mapping of the metabolic response to an energy deficit remain largely unknown. Recent studies have identified the medial preoptic area of the hypothalamus (MPO) as the central regulator of torpor. MPO neurons that express estrogen receptor alpha have been identified as central coordinators of torpor, and MPO neurons that are activated during torpor broadly express estrogen receptors, suggesting that circulating estrogens may directly modulate torpor-driving neurons in the MPO. To test the hypothesis that circulating estrogens inhibit torpor by acting directly on estrogen-sensitive neurons in the MPO, we delivered 17β-estradiol (E2) directly to the MPO before inducing torpor with a 48-hour fast. Surprisingly, we found that E2 delivered to the MPO was suffcient to inhibit fasting-induced torpor in gonad-intact, but not ovariectomized, female mice. These data demonstrate that E2 signaling in the MPO is insuffcient to inhibit torpor on its own and that there are likely MPO-independent nodes in the body that circulating estrogens act on to inhibit torpor. However, our data also demonstrate that E2 signaling in the MPO does play a role in tuning the torpor response when endogenous gonadal hormones are present, suggesting that the MPO can sense estrogens and engage the appropriate effector circuits to inhibit torpor in certain physiological contexts. Together, these data advance our understanding of how circulating estrogens inhibit torpor in mice — a critical step towards the broader goal of understanding how circulating estrogens influence energy expenditure, and how these pathways can be manipulated to improve metabolic health. NIH RO1 (R01AG066821) - "Estrogenic modulation of neural circuits that control temperature" AHA Predoctoral Fellowship (23PRE1019923) - Estrogenic modulation of hypothalamic neurons that control energy expenditure. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Computer vision analysis of mother-infant interaction identified efficient pup retrieval in V1b receptor knockout mice

Close contact between lactating rodent mothers and their infants is essential for effective nursing. Whether the mother’s effort to retrieve the infants to their nest requires the vasopressin-signaling via V1b receptor has not been fully defined. To address this question, V1b receptor knockout (V1bKO) and control mice were analyzed in pup retrieval test. Because an exploring mother in a new test cage randomly accessed to multiple infants in changing backgrounds over time, a computer vision-based deep learning analysis was applied to continuously calculate the distances between the mother and the infants as a parameter of their relationship. In an open-field, a virgin female V1bKO mice entered fewer times into the center area and moved shorter distances than wild-type (WT). While this behavioral pattern persisted in V1bKO mother, the pup retrieval test demonstrated that total distances between a V1bKO mother and infants came closer in a shorter time than with a WT mother. Moreover, in the medial preoptic area, parts of the V1b receptor transcripts were detected in galanin- and c-fos-positive neurons following maternal stimulation by infants. This research highlights the effectiveness of deep learning analysis in evaluating the mother-infant relationship and the critical role of V1b receptor in pup retrieval during the early lactation phase.

Poweromin X Ten, a polyherbal formulation improves male sexual function: In vivo and network pharmacology study

Introduction Poweromin X Ten (PXT) is a polyherbal formulation, traditionally used to enhance male sexual function. However, the safety and benefits of PXT have not been scientifically evaluated. Therefore, the present study investigated the toxicity and aphrodisiac potential of PXT in male rats and explored its principal mechanisms of action. Methods Male Wistar rats were orally administered PXT (50 or 100 mg/kg) for 28 days, and sexual activity parameters, including latency and frequency of mounting and intromissions, were studied. The reproductive toxicity and spermatogenic potential were also examined. Furthermore, dopamine and serotonin levels in brain regions associated with sexual activity were assessed. Network analysis was used to identify the key bioactive compounds and their core targets involved in their beneficial actions. Results Treatment with PXT improved sexual activity in male rats, as evidenced by reduced mounting and intromission latency and a significant increase in mount frequency. Moreover, PXT exhibited spermatogenic potential and did not induce reproductive toxicity. Notably, treatment with 50 mg/kg PXT elevated dopamine levels in median preoptic area and hypothalamus. Pathway analysis indicated that PXT primarily modulated the PI3K-Akt, calcium, and MAPK signalling pathways to enhance male sexual function. Network analysis identified macelignan, β-estradiol, testosterone, and paniculatine as key bioactive components of PXT, which likely act through core targets, such as androgen receptor (AR), Mitogen-activated protein kinase 3 (MAPK3), epidermal growth factor receptor (EGFR), estrogen receptor 1 (ESR1), and vascular endothelial growth factor (VEGF) to facilitate the improvement of male sexual function. Conclusion Study results suggest that PXT is a safer alternative with aphrodisiac and spermatogenic potential. These effects are partly attributed to the enhanced dopamine levels in the brain. Furthermore, this study provides insights into the specific signalling pathways and bioactive compounds that underlie the improvements in male sexual function associated with PXT.