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.

Synthetic torpor confers cardioprotection against myocardial ischaemia/reperfusion injury in the rat

Abstract Introduction Torpor is a hypothermic, bradycardic, hypometabolic state enabling animals, such as mice, to survive in unfavourable environmental conditions such as cold exposure or reduced food availability. It is thought to be a cardioprotective state. There is interest in developing models that mimic aspects of torpor in clinical settings such as ischaemia-reperfusion injury. The preoptic area of the hypothalamus (POA) has emerged as a key centre for triggering torpor in the mouse. Purpose Induce a synthetic torpor-like state in a species that does not naturally enter torpor (the rat) by chemoactivation of neurons in the POA that correspond to those that induce torpor in the mouse. Test the cardioprotective effects of synthetic torpor in the Langendorff ischaemia-reperfusion preparation. Methods Designer receptors exclusively activated by designer drugs (DREADDs) were used to exogenously activate excitatory neurons in the POA of the rat hypothalamus. Viral vectors (pAAV-CaMKIIa-hM3D(Gq)-mCherry) were stereotaxically injected bilaterally into the POA under ketamine and medetomidine anaesthesia, resulting in expression of DREADDs in excitatory neurons. Control animals received a vector delivering the gene for a fluorescent protein only. DREADD receptors in transfected neurons were activated by subsequent injection of Clozapine-N-Oxide (CNO, 2mg/kg IP), which results in neuronal activation and induces synthetic torpor. Heart rate and core temperature were monitored using implanted telemeters. 2 weeks after vector injection, animals were anaesthetised using 5% isoflurane and culled by cervical dislocation. Hearts were excised and ex-vivo whole heart perfusion at 37°C was performed using the Langendorff apparatus. Hearts were subjected to 30 minutes of global warm ischaemia followed by 60 minutes of reperfusion. Hearts were stained using tetrazolium triphenyl chloride, and infarct size as a proportion of the total heart area calculated. Results Chemoactivation of rat POA neurons induced synthetic torpor characterised by bradycardia (pre: 341.0 ± 17.73bpm, post: 233.4 ± 20.47bpm, paired t (4) = 5.4791, p = .0054) and hypothermia (36.2 ±0.40°C vs 31.6 ± 0.55°C (paired t (4) = 7.9023, p = .0014). CNO had no effect on heart rate or core temperature in control animals. The mean infarct size was significantly lower in synthetic torpor (21.54 ±2.84%) compared to control hearts (29.62 ±2.59%) (unpaired t (23) = 2.1054, p = .0464). Conclusions Synthetic torpor, induced centrally in a species for which torpor is not a natural behaviour, confers striking cardioprotection in an ex-vivo ischaemia-reperfusion model. This novel approach to cardioprotection against myocardial ischaemia/reperfusion injury should be further investigated as a potential therapeutic target for use in clinical practice.

Early perturbations to fluid homeostasis alter development of hypothalamic feeding circuits with context-specific changes in ingestive behavior.

Drinking and feeding are tightly coordinated homeostatic events and the paraventricular nucleus of the hypothalamus (PVH) represents a possible node of neural integration for signals related to energy and fluid homeostasis. We used TRAP2;Ai14 and Fos labeling to visualize neurons in the PVH and median preoptic nucleus (MEPO) responding to both water deprivation and hunger. Moreover, we determined that structural and functional development of dehydration-sensitive inputs to the PVH from the MEPO precedes those of agouti-related peptide (AgRP) neurons, which convey hunger signals and are known to be developmentally programmed by nutrition. We also determined that osmotic hyperstimulation of neonatal mice led to enhanced AgRP inputs to the PVH in adulthood, as well as disruptions to ingestive behaviors during high-fat diet feeding and dehydration-anorexia. Thus, development of feeding circuits is impacted not only by nutritional signals, but also by early perturbations to fluid homeostasis with context-specific consequences for coordination of ingestive behavior.

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

7934 Tac1-expressing cells in the central premammillary nucleus are essential for induction of the pre-ovulatory LH surge

Abstract Disclosure: S. Leon: None. M. Navarro: None. C. Perdices-Lopez: None. I. Velasco Aguayo: None. E. Torres Jimenez: None. D. Garcia-Galiano: None. V.M. Navarro: None. M. Tena-Sempere: None. Infertility/subfertility is a growing challenge in reproductive medicine. The most common cause of subfertility in females is ovulatory dysfunction. Conditions linked with oligo-/anovulation include polycystic ovary syndrome, hypothalamic amenorrhea and premature ovarian insufficiency. However, the central neuro-endocrine defects affecting the pre-ovulatory LH surge that drives ovulation remain ill defined. While hypothalamic GnRH neurons are the major output pathway for the brain control of ovulation, upstream Kiss1 neurons, particularly in the anteroventral periventricular area (AVPV) of the hypothalamus in rodents, are thought to be crucial for the timed activation of GnRH neurons and generation of the preovulatory surge of gonadotropins. Yet, the major upstream regulators of this Kiss1/GnRH pathway are largely unknown. Substance P (SP, encoded by Tac1), a member of the tachykinin (TAC) family that acts via the receptor, NK1R (encoded by Tacr1), has been shown to centrally regulate gonadotropin release, and, according to our initial data, might modulate the pre-ovulatory surge in mice through its direct action on AVPV Kiss1 neurons. We report herein that Tac1-expressing cells in the ventral premammillary nucleus (PMV) become activated during the preovulatory surge, as denoted by co-expression of c-Fos. Moreover, we document here that these neurons project to key reproductive areas, including the rostral preoptic area (rPOA), AVPV, arcuate nucleus (ARC), and the medial posterodorsal amygdala (MePD). Furthermore, the chemogenetic inhibition of Tac1-expressing neurons in the PMV dramatically decreases the magnitude of the pre-ovulatory LH surge, but has no influence on tonic LH pulsatility. Overall, our findings strongly support a relevant stimulatory role of SP originating from Tac1 neurons at the PMV in the generation of the pre-ovulatory surge of gonadotropins, responsible for ovulation. 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.

8574 Single-Cell Assessment of Gene Expression of the Tuberal Hypothalamus and Preoptic Area From Birth to Puberty in Male and Female Mice

8574 Single-Cell Assessment of Gene Expression of the Tuberal Hypothalamus and Preoptic Area From Birth to Puberty in Male and Female Mice

Sleepless nights and social plights: medial septum GABAergic hyperactivity in a neuroligin 3-deficient autism model.

Social deficits represent a core symptom domain of autism spectrum disorder (ASD), which is often comorbid with sleep disturbances. In this issue of the JCI, Sun et al. explored a medial septum (MS) circuit linking these behaviors in a neuroligin 3 conditional knockout model of autism. They identified GABAergic neuron hyperactivity following neuroligin 3 deletion in the MS. This hyperactivity resulted in the inhibition of the downstream preoptic area (POA) and hippocampal CA2 region, resulting in sleep loss and social memory deficits, respectively. Inactivating the hyperactive MS GABA neurons or activating the POA or CA2 rescued the behavioral deficits. Together, these findings deepen our understanding of neural circuits underlying social and sleep deficits in ASD.

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.

Identification of a neuropeptide in suppressing food intake in zebrafish

Neuropeptides play crucial roles in regulating various physiological processes in vertebrates. In this study, we identified a novel neuropeptide-encoding gene, nwk, in the genomes of some vertebrate species. The nwk cDNA was subsequently cloned from the brain of zebrafish. The Nwk precursor comprises 88 amino acids, with a putative mature peptide (Nwk-22) of 22 amino acids. Sequence analysis revealed that Nwk-22 is relatively conserved across vertebrate species. Nwk is predominantly expressed in the brain, with positive mRNA cells identified in the TPp and preoptic area. Intraperitoneal injection of Nwk-22 suppressed food intake and downregulated the mRNA expression of the orexigenic factor agouti-related peptide (agrp) in zebrafish. Additionally, a CRISPR/Cas9 approach was used to generate nwk mutant zebrafish. The nwk−/− zebrafish exhibited increased food consumption compared to wild-type controls. Furthermore, Nwk-22a injection in nwk−/− fish also suppressed agrp expression while stimulating the expression of the anorexigenic gene pomca, further supporting the anorexigenic role of Nwk. Taken together, these findings suggest that Nwk functions as an anorexigenic factor, reducing food intake by downregulating orexigenic genes like agrp and upregulating anorexigenic genes like pomc in zebrafish.

The telencephalon is a neuronal substrate for systemic inflammatory responses in teleosts via polyamine metabolism

Systemic inflammation elicits sickness behaviors and fever by engaging a complex neuronal circuitry that begins in the preoptic area of the hypothalamus. Ectotherms such as teleost fish display sickness behaviors in response to infection or inflammation, seeking warmer temperatures to enhance survival via behavioral fever responses. To date, the hypothalamus is the only brain region implicated in sickness behaviors and behavioral fever in teleosts. Yet, the complexity of neurobehavioral manifestations underlying sickness responses in teleosts suggests engagement of higher processing areas of the brain. Using in vivo models of systemic inflammation in rainbow trout, we find canonical pyrogenic cytokine responses in the hypothalamus whereas in the telencephalon and the optic tectum il-1b and tnfa expression is decoupled from il-6 expression. Polyamine metabolism changes, characterized by accumulation of putrescine and decreases in spermine and spermidine, are recorded in the telencephalon but not hypothalamus upon systemic injection of bacteria. While systemic inflammation causes canonical behavioral fever in trout, blockade of bacterial polyamine metabolism prior to injection abrogates behavioral fever, polyamine responses, and telencephalic but not hypothalamic cytokine responses. Combined, our work identifies the telencephalon as a neuronal substrate for brain responses to systemic inflammation in teleosts and uncovers the role of polyamines as critical chemical mediators in sickness behaviors.

Preoptic area controls sleep-related seizure onset in a genetic epilepsy mouse model.

In genetic and refractory epileptic patients, seizure activity exhibits sleep-related modulation/regulation and sleep and seizure are intermingled. In this study, by using one het Gabrg2 Q390X KI mice as a genetic epilepsy model and optogenetic method in vivo , we found that subcortical POA neurons were active within epileptic network from the het Gabrg2 Q390X KI mice and the POA activity preceded epileptic (poly)spike-wave discharges(SWD/PSDs) in the het Gabrg2 Q390X KI mice. Meanwhile, as expected, the manipulating of the POA activity relatively altered NREM sleep and wake periods in both wt and the het Gabrg2 Q390X KI mice. Most importantly, the short activation of epileptic cortical neurons alone did not effectively trigger seizure activity in the het Gabrg2 Q390X KI mice. In contrast, compared to the wt mice, combined the POA nucleus activation and short activation of the epileptic cortical neurons effectively triggered or suppressed epileptic activity in the het Gabrg2 Q390X KI mice, indicating that the POA activity can control the brain state to trigger seizure incidence in the het Gabrg2 Q390X KI mice in vivo. In addition, the suppression of POA nucleus activity decreased myoclonic jerks in the Gabrg2 Q390X KI mice. Overall, this study discloses an operational mechanism for sleep-dependent seizure incidence in the genetic epilepsy model with the implications for refractory epilepsy. This operational mechanism also underlies myoclonic jerk generation, further with translational implications in seizure treatment for genetic/refractory epileptic patients and with contribution to memory/cognitive deficits in epileptic patients.

Sex-specific hypothalamic neuropathology and glucose metabolism in an amyloidosis transgenic mouse model of Alzheimer’s disease

BackgroundAmyloid toxicity and glucose metabolic disorders are key pathological features during the progression of Alzheimer’s disease (AD). While the hypothalamus plays a crucial role in regulating systemic energy balance, the distribution of amyloid plaques in the preoptic, anterior, tuberal, and mammillary regions of the hypothalamus in AD mice, particularly across both sexes, remains largely unclear. Our ongoing research aims to explore hypothalamic neuropathology and glucose metabolic disturbances in a well-described APP/PS1 mouse model of AD.ResultsImmunocytochemical staining revealed that Old-AD-Female mice exhibited a greater hypothalamic Amyloid β (Aβ) burden than their Old-AD-Male counterparts, with the mammillary bodies showing the most severe accumulation. Analysis of ionized calcium binding adaptor molecule 1 (IBA1) immunoreactivity and Iba1 mRNA indicated differential microgliosis based on sex, while tanycytic territory and ZO-1 tight junction protein expression remained stable in AD mice. Moreover, sex-specific peripheral glucose metabolic parameters (random and fasting blood glucose) seemed to be exacerbated by age. Old AD mice of both sexes exhibited limited hypothalamic activation (c-Fos + cells) in response to blood glucose fluctuations. Hypothalamic Glut 1 expression decreased in young but increased in old female AD mice compared with age-matched male AD mice. Pearson correlation analysis further supported a negative correlation between hypothalamic Aβ load and random blood glucose in old AD groups of both genders, shedding light on the mechanisms underlying this amyloidosis mouse model.ConclusionAged APP/PS1 mice exhibit sex-specific hypothalamic neuropathology and differential glucose metabolism, highlighting distinct pathological mechanisms within each gender.

Divergent neural nodes are species- and hormone-dependent in the brood parasitic brain.

Avian brood parasitism is an evolutionarily derived behavior for which the neurobiological mechanisms are mostly unexplored. We aimed to identify brain regions that have diverged in the brood-parasitic brain using relative transcript abundance of social neuropeptides and receptors. We compared behavioral responses and transcript abundance in three brain regions in the brown-headed cowbird (BHCO), a brood parasite, and a closely related parental species, the red-winged blackbird (RWBL). Females of both species were treated with mesotocin (MT; avian homolog of oxytocin) or saline prior to exposure to nest stimuli. Results reveal that MT promotes approach toward nests with eggs rather than nests with begging nestlings in both species. We also examined relative transcript abundance of the five social neuropeptides and receptors in the brain regions examined: preoptic area (POA), paraventricular nucleus (PVN) and bed nucleus of the stria terminalis (BST). We found that MT-treated cowbirds but not blackbirds exhibited lower transcript abundance for two receptors, corticotropin-releasing factor 2 (CRFR2) and prolactin receptor (PRLR) in BST. Additionally, MT-treated cowbirds had higher PRLR in POA, comparable to those found in blackbirds, regardless of treatment. No other transcripts of interest exhibited significant differences as a result of MT treatment, but we found a significant effect of species in the three regions. Together, these results indicate that POA, PVN, and BST represent neural nodes that have diverged in avian brood parasites and may serve as neural substrates of brood-parasitic behavior.

Kynurenic Acid Modulates the Expression of Genes and the Activity of Cellular Antioxidant Enzymes in the Hypothalamus and Hippocampus in Sheep.

Kynurenic acid (KYNA), a tryptophan metabolite, is believed to exert neuromodulatory and neuroprotective effects in the brain. This study aimed to examine KYNA's capacity to modify gene expression and the activity of cellular antioxidant enzymes in specific structures of the sheep brain. Anestrous sheep were infused intracerebroventricularly with two KYNA doses-lower (4 × 5 μg/60 μL/30 min, KYNA20) and higher (4 × 25 μg/60 μL/30 min, KYNA100)-at 30 min intervals. The abundance of superoxide dismutase 2 (SOD2), catalase (CAT), and glutathione peroxidase 1 (GPx1) mRNA, as well as enzyme activities, were determined in the medial-basal hypothalamus (MBH), the preoptic (POA) area of the hypothalamus, and in the hippocampal CA1 field. Both doses of KYNA caused a decrease (p < 0.01) in the expression of SOD2 and CAT mRNA in all structures examined compared to the control group (except for CAT in the POA at the KYNA100 dose). Furthermore, lower levels of SOD2 mRNA (p < 0.05) and CAT mRNA (p < 0.01) were found in the MBH and POA and in the POA and CA, respectively, in sheep administered with the KYNA20 dose. Different stimulatory effects on GPx1 mRNA expression were observed for both doses (p < 0.05-p < 0.01). KYNA exerted stimulatory but dose-dependent effects on SOD2, CAT, and GPx1 activities (p < 0.05-p < 0.001) in all brain tissues examined. The results indicate that KYNA may influence the level of oxidative stress in individual brain structures in sheep by modulating the expression of genes and the activity of at least SOD2, CAT, and GPx1. The present findings also expand the general knowledge about the potential neuroprotective properties of KYNA in the central nervous system.

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.