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Sleep disruption is a frequent problem of advancing age, often accompanied by low-grade chronic central and peripheral inflammation. We examined whether chronic neuroinflammation in the preoptic and basal forebrain area (POA-BF), a critical sleep-wake regulatory structure, contributes to this disruption. We developed a targeted viral vector designed to overexpress tumor necrosis factor-alpha (TNFα), specifically in astrocytes (AAV5-GFAP-TNFα-mCherry), and injected it into the POA of young mice to induce heightened neuroinflammation within the POA-BF. Compared to the control (treated with AAV5-GFAP-mCherry), mice with astrocytic TNFα overproduction within the POA-BF exhibited signs of increased microglia activation, indicating a heightened local inflammatory milieu. These mice also exhibited aging-like changes in sleep-wake organization and physical performance, including (a) impaired sleep-wake functions characterized by disruptions in sleep and waking during light and dark phases, respectively, and a reduced ability to compensate for sleep loss; (b) dysfunctional VLPO sleep-active neurons, indicated by fewer neurons expressing c-fos after suvorexant-induced sleep; and (c) compromised physical performance as demonstrated by a decline in grip strength. These findings suggest that inflammation-induced dysfunction of sleep- and wake-regulatory mechanisms within the POA-BF may be a critical component of sleep-wake disturbances in aging.

Context The neuropeptide RFRP-3 (RFamide-related peptide-3) is thought to play a role in the negative regulation of fertility. However, the exogenous administration of RFRP-3 yields varying results depending on the dose and route of administration, sex of the subject, and many other variables. Manipulation of in vivo neuronal activity using DREADDs (designer receptor exclusively activated by designer drugs) technology enables investigation of cell type–specific neuronal activation in a manner that better reflects endogenous neuronal activity. Objective To test the effects of RFRP neuronal activation on pulsatile luteinizing hormone (LH) secretion. Methods We generated mice expressing the stimulatory hM3Dq designer receptor exclusively in RFRP cells using 2 different Cre-loxP–mediated approaches: (1) we bred mice to express hM3Dq in all Rfrp -Cre-expressing cells, including some that transiently expressed Rfrp -Cre neonatally (RFRP × hM3Dq mice), and (2) we stereotaxically injected Cre-dependent hM3Dq into the dorsomedial nucleus of RFRP-Cre mice to drive hM3Dq expression exclusively in a subpopulation of adult Rfrp -Cre neurons (RFRP-AAV-hM3Dq mice). We then investigated the effects of acute hM3Dq activation on LH pulse frequency in RFRP × hM3Dq mice, RFRP-AAV-hM3Dq mice, and their respective controls. Results In both female RFRP × hM3Dq and RFRP-AAV-hM3Dq mice, chemogenetic activation of Cre-driven hM3Dq led to a significant 35% to 50% reduction in LH pulse frequency compared with controls, while no differences in pulse amplitude or mean LH concentration were observed. In marked contrast, RFRP activation did not cause any changes to LH pulse dynamics in male mice. Conclusions These data show for the first time that activation of neurons that have expressed Rfrp , or of a subset of adult RFRP neurons, can independently suppress LH pulsatility in female, but not male mice. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: The circuitry underlying the initiation, maintenance, and coordination of wakefulness, rapid eye movement sleep, and non‐rapid eye movement sleep is not thoroughly understood. Sleep is thought to arise due to decreased activity in the ascending reticular arousal system, which originates in the brainstem and awakens the thalamus and cortex during wakefulness. Despite the conventional association of sleep–wake states with hippocampal rhythms, the mutual influence of the hippocampal formation in regulating vigilance states has been largely neglected. Here, we focus on the subiculum, the main output region of the hippocampal formation. The subiculum, particulary the ventral part, sends extensive monosynaptic projections to crucial regions implicated in sleep–wake regulation, including the thalamus, lateral hypothalamus, tuberomammillary nucleus, basal forebrain, ventrolateral preoptic nucleus, ventrolateral tegmental area, and suprachiasmatic nucleus. Additionally, second‐order projections from the subiculum are received by the laterodorsal tegmental nucleus, locus coeruleus, and median raphe nucleus, suggesting the potential involvement of the subiculum in the regulation of the sleep–wake cycle. We also discuss alterations in the subiculum observed in individuals with sleep disorders and in sleep‐deprived mice, underscoring the significance of investigating neuronal communication between the subiculum and pathways promoting both sleep and wakefulness. [ABSTRACT FROM AUTHOR]

Context: Understanding of central nervous system mechanisms related to age-related infertility remains limited. Fibril α-synuclein, distinct from its monomer form, is implicated in age-related diseases and propagates among neurons akin to prions. Aims: We compared α-synuclein expression in gonadotropin-releasing hormone-expressing neurons (GnRH neurons) in the pre-optic area, arcuate nucleus, and median eminence of healthy heifers and aged cows to determine its role in age-related infertility. Methods: We analysed mRNA and protein expression, along with fluorescent immunohistochemistry for GnRH and α-synuclein, followed by Congo red staining to detect amyloid deposits, and confocal microscopy. Key results: Both mRNA and protein expressions of α-synuclein were confirmed by reverse transcription-polymerase chain reaction (RT-PCR) and western blots in bovine cortex, hippocampus, and anterior and posterior hypothalamus tissues. Significant differences in α-synuclein mRNA expression were observed in the cortex and hippocampus between young and old cows. Western blots showed five bands of α-synuclein, probably reflecting monomer, dimer, and oligomers, in the cortex, hippocampus, hypothalamus tissues, and there were significant differences in some bands between young and old cows. Bright-field and polarised light microscopy did not detect obvious amyloid deposition in aged hypothalami; however, higher-sensitive confocal microscopy unveiled strong positive signal of Congo red and α-synuclein in GnRH neurons in aged hypothalami. Additionally, α-synuclein expression was detected in immortalised GnRH neurons, GT1-7 cells. Conclusion: Alpha-synuclein was expressed in GnRH neurons, and some differences were observed between young and old hypothalami. Implications: Alpha-synuclein may play an important role in aging-related infertility. In our investigation into age-related infertility, we examined the presence of α-synuclein, a protein associated with brain aging, particularly in gonadotropin-releasing hormone (GnRH) neurons in hypothalami. Contrasting samples from young and old cows, we observed significant differences in α-synuclein levels across the specific hypothalamus regions linked to reproductive function. These findings suggest that α-synuclein may play a pivotal role in the mechanisms underlying age-related infertility, paving the way for further inquiries into potential therapeutic avenues in reproductive health. Image by Hiroya Kadokawa. [ABSTRACT FROM AUTHOR]

Gonadotropin releasing hormone (GnRH) synthesis and secretion regulates seasonal fertility. In the brain, the distribution of GnRH-positive neurons is diffuse, hindering efforts to monitor variations in its cellular and tissue levels. Here, we aim at assessing GnRH immunoreactivity in nuclei responsible for seasonal fertility regulation (SFR) within the posterior, anterior, and preoptic areas of the basal hypothalamus during estrous in ewes. We detected reaction products in the ventromedial basal hypothalamus in neurons, nerve fibers, non-neuronal immunoreactive bodies, and diffuse interstitial areas. Immunoreactivity correlated with the distribution of the main SFR nuclei in the arcuate, retrochiasmatic, periventricular, medial preoptic, supraoptic, and preoptic areas. By independent component analysis density segmentation and by interferential contrast, we identified GnRH non-neuronal positive bodies as microglial cells encapsulated within a dense halo of reaction products. These GnRH-positive microglial cells were distributed in patches and rows throughout the basal ventromedial hypothalamus, suggesting their role in paracrine or juxtacrine signaling. Moreover, as shown by ionized calcium-binding adaptor molecule 1 (IBA1) immunocytochemistry, the distribution of GnRH reaction products overlapped with the microglial dense reactive zones. Therefore, our findings support the assertion that a combined densitometric analysis of GnRH and IBA1 immunocytochemistry enables activity mapping for monitoring seasonal changes following experimental interventions. • GnRH reaction products overlap with areas of reactive microglia in the basal ventromedial hypothalamus of ewes. • GnRH-positive microglial cells support their role in activity-dependent juxtacrine signaling. • Comparative densitometric mapping of GnRH and IBA1 may be a suitable method for monitoring seasonal changes. [ABSTRACT FROM AUTHOR]

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. Whether excitatory and inhibitory neural populations in the medial preoptic area of hypothalamus (MPOA) respond differentially under different chronic stress conditions is not fully understood. Here, the authors show that chronic stress induces a disruption of excitation-inhibition balance in mouse MPOA, leading to depression-like states. [ABSTRACT FROM AUTHOR]

Our body temperature is normally kept within a narrow range of 1°C. For example, if our body temperature rises, such as in a hot environment or due to strenuous exercise, our thermoregulatory system will trigger a powerful heat defense response with vasodilation, sweating, and lowered metabolism. During fever, which often involves body temperatures of up to 41°C, this heat defense mechanism is apparently inhibited; otherwise, the rising body temperature would be immediately combated, and fever would not be allowed to develop. New evidence suggests how and where this inhibition takes place. In two consecutive studies from Cheng et al. and Xu et al., it has been shown that prostaglandin E2, which generates fever by acting on thermosensory neurons in the preoptic hypothalamus, also acts on neurons in the brainstem parabrachial nucleus, which receive temperature information from temperature-activated spinal cord neurons and relay this information to the thermoregulatory center in the hypothalamus to either induce cold or heat defenses. By acting on the same type of prostaglandin E2 receptor that is critical for fever generation in the preoptic hypothalamus, the EP3 receptor, prostaglandin E2 inhibits the signaling of the heat-responsive parabrachial neurons, while stimulating the cold-responsive neurons. These novel findings thus show that prostaglandin E2, by binding to the same receptor subtype in the parabrachial nucleus as in the preoptic hypothalamus, adjusts the sensitivity of the thermosensory system in a coordinated manner to allow the development of febrile body temperatures. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Multiple embryonic origins give rise to forebrain oligodendrocytes (OLs), yet controversies and uncertainty exist regarding their differential contributions. We established intersectional and subtractional strategies to genetically fate map OLs produced by medial ganglionic eminence/ preoptic area (MGE/POA), lateral/caudal ganglionic eminences (LGE/CGE), and dorsal pallium in the mouse brain. We found that, contrary to the canonical view, LGE/CGE-derived OLs make minimum contributions to the neocortex and corpus callosum, but dominate piriform cortex and anterior commissure. Additionally, MGE/POA-derived OLs, instead of being entirely eliminated, make small but sustained contribution to cortex with a distribution pattern distinctive from those derived from the dorsal origin. Our study provides a revised and more comprehensive view of cortical and white matter OL origins, and established valuable new tools and strategies for future OL studies. [ABSTRACT FROM AUTHOR]

Simple Summary: The ecdysis of arthropods is an essential process for survival, growth, and reproduction. Independent molting behavior is widely adopted by most arthropods, but synchronous molting behavior is uncommon in some groups of arthropods. Synchronous molting behavior is sometimes caused by stimuli from the physical environment and food supply and sometimes involves social facilitation. As some of the earliest terrestrial arthropods, newborn scorpions exhibit unique synchronous molting behavior induced by social facilitation based on maternal care and reciprocal aggregation. Before molting, strong maternal care provided by mother scorpions helps newborn scorpions climb onto her back, which results in a survival rate of approximately 100% after molting. Moreover, aggregate molting behavior greatly increases the survival rate of newborn scorpions via collaborative molting by enabling the interconnection of pedipalps, legs, or tails among the scorpions, whether they are on the back of the mother scorpion or not. Our results highlight the novel role of social facilitation based on maternal care and reciprocal aggregation during the simultaneous molting of arthropods, which markedly enhances our knowledge of the extraordinary survival strategy of ancient arthropods during the molting process. Ecdysis is a well-known developmental feature among arthropods. Because the aggregate and synchronous molting of first-instar scorpions is markedly different from the common independent molting behavior of older scorpions and most arthropods, knowledge on the biological benefits of the unusual behavior of first-instar scorpions remain limited. Before the molting of newborn scorpions, their mothers exhibited a remarkable ability to efficiently locate the fallen offspring and help them climb onto their back, which was supported by strong maternal behavior because they climbed more swiftly than the 7-day postpartum scorpions. Most newborn scorpions molted and survived on the mother's back, with a survival rate of approximately 100%, and most newborn scorpions survived via aggregate molting behavior on sand in the absence of mothers (89.83% ± 1.91%). The important role of the mother scorpion was further highlighted in mothers with one to five first-instar scorpions. While all first-instar scorpions individually or reciprocally molted and survived on the mother's back, only 52.00% ± 7.14% to 79.20% ± 4.24% of newborn scorpions isolated from the mother could individually or reciprocally molt and survive on the sand, and the aggregated states of first-instar scorpions strengthened as their numbers on sand increased before molting. These results highlight collaborative molting as an evolutionary driving force for newborn scorpions. Taken together, both maternal care and collaborative aggregate molting behavior enhanced the survival of first-instar scorpions before and after molting, and these benefits for first-instar scorpions play essential and evolutionary roles in scorpion survival. [ABSTRACT FROM AUTHOR]

Aim: Animals exhibit physiological changes designed to eliminate the perceived danger, provoking similar symptoms of fever. However, a high‐grade fever indicates poor clinical outcomes. Caspase11 (Casp11) is involved in many inflammatory diseases. Whether Casp11 leads to fever remains unclear. In this study, we investigate the role of the preoptic area of the hypothalamus (PO/AH) microglia Casp11 in fever. Methods: We perform experiments using a rat model of LPS‐induced fever. We measure body temperature and explore the functions of peripheral macrophages and PO/AH microglia in fever signaling by ELISA, immunohistochemistry, immunofluorescence, flow cytometry, macrophage depletion, protein blotting, and RNA‐seq. Then, the effects of macrophages on microglia in a hyperthermic environment are observed in vitro. Finally, adeno‐associated viruses are used to knockdown or overexpress microglia Casp11 in PO/AH to determine the role of Casp11 in fever. Results: We find peripheral macrophages and PO/AH microglia play important roles in the process of fever, which is proved by macrophage and microglia depletion. By RNA‐seq analysis, we find Casp11 expression in PO/AH is significantly increased during fever. Co‐culture and conditioned‐culture simulate the induction of microglia Casp11 activation by macrophages in a non‐contact manner. Microglia Casp11 knockdown decreases body temperature, pyrogenic factors, and inflammasome, and vice versa. Conclusion: We report that Casp11 drives fever. Mechanistically, peripheral macrophages transmit immune signals via cytokines to microglia in PO/AH, which activate the Casp11 non‐canonical inflammasome. Our findings identify a novel player, the microglia Casp11, in the control of fever, providing an explanation for the transmission and amplification of fever immune signaling. [ABSTRACT FROM AUTHOR]

It is suggested that cannabinoids (CBs) may disturb reproduction through action on hypothalamic gonadotropin-releasing hormone (GnRH) neurons directly or indirectly through intermediates such as prostaglandins. The study aimed to determine the influence of intracerebroventricular (i.c.v.) injection of the endogenous cannabinoid anandamide (N-arachidonoylethanolamine – AEA), alone or with the prostaglandin synthesis inhibitor indomethacin (IND), on GnRH/luteinising hormone (LH) secretion. The purpose of the research was to clarify the role of endocannabinoids and their interaction with prostaglandins in the regulation of reproduction at the level of the hypothalamus and pituitary in anoestrous sheep. The study was performed on 24 anoestrous ewes divided into four experimental groups: a control group receiving i.c.v. injection of Ringer–Locke solution, an AEA group that received i.c.v. injection of 30 μM of AEA, an IND group receiving i.c.v. injection of 5 μM of IND and an AEA + IND group that received i.c.v. injections of 30 μM of AEA and 5 μM of IND. Anandamide stimulated GnRH protein and gene expression in the median eminence and protein expression in the preoptic area without influencing GnRH messenger RNA (mRNA) in this structure. Indomethacin reversed the changes in GnRH secretion after AEA administration. It was also found that AEA stimulated LH mRNA in the pituitary without influencing LH release. Our results support the role of endogenous cannabinoids in the regulation of reproductive processes at the central nervous system level. They may act directly on the hypothalamic GnRH neurons or indirectly through intermediates such as prostaglandins. [ABSTRACT FROM AUTHOR]

Psychological stress is linked to infertility by suppressing the hypothalamic GnRH pulse generator. The posterodorsal subnucleus of the medial amygdala (MePD) is an upstream regulator of GnRH pulse generator activity and displays increased neuronal activation during psychological stress. The MePD is primarily a GABAergic nucleus with a strong GABAergic projection to hypothalamic reproductive centers; however, their functional significance has not been determined. We hypothesize that MePD GABAergic signalling mediates psychological stress–induced suppression of pulsatile LH secretion. We selectively inhibited MePD GABA neurons during psychological stress in ovariectomized (OVX) Vgat-cre-tdTomato mice to determine the effect on stress-induced suppression of pulsatile LH secretion. MePD GABA neurons were virally infected with inhibitory hM4DGi-designer receptor exclusively activated by designer drugs (DREADDs) to selectively inhibit MePD GABA neurons. Furthermore, we optogenetically stimulated potential MePD GABAergic projection terminals in the hypothalamic arcuate nucleus (ARC) and determined the effect on pulsatile LH secretion. MePD GABA neurons in OVX female Vgat-cre-tdTomato mice were virally infected to express channelrhodopsin-2 and MePD GABAergic terminals in the ARC were selectively stimulated by blue light via an optic fiber implanted in the ARC. DREADD-mediated inhibition of MePD GABA neurons blocked predator odor and restraint stress-induced suppression of LH pulse frequency. Furthermore, sustained optogenetic stimulation at 10 and 20 Hz of MePD GABAergic terminals in the ARC suppressed pulsatile LH secretion. These results show for the first time that GABAergic signalling in the MePD mediates psychological stress–induced suppression of pulsatile LH secretion and suggest a functionally significant MePD GABAergic projection to the hypothalamic GnRH pulse generator. [ABSTRACT FROM AUTHOR]

Abstract Background Sexual differentiation of the brain occurs in all major vertebrate lineages but is not well understood at a molecular and cellular level. Unlike most vertebrates, sex-changing fishes have the remarkable ability to change reproductive sex during adulthood in response to social stimuli, offering a unique opportunity to understand mechanisms by which the nervous system can initiate and coordinate sexual differentiation. Methods This study explores sexual differentiation of the forebrain using single nucleus RNA-sequencing in the anemonefish Amphiprion ocellaris, producing the first cellular atlas of a sex-changing brain. Results We uncover extensive sex differences in cell type-specific gene expression, relative proportions of cells, baseline neuronal excitation, and predicted inter-neuronal communication. Additionally, we identify the cholecystokinin, galanin, and estrogen systems as central molecular axes of sexual differentiation. Supported by these findings, we propose a model of sexual differentiation in the conserved vertebrate social decision-making network spanning multiple subtypes of neurons and glia, including neuronal subpopulations within the preoptic area that are positioned to regulate gonadal differentiation. Conclusions This work deepens our understanding of sexual differentiation in the vertebrate brain and defines a rich suite of molecular and cellular pathways that differentiate during adult sex change in anemonefish.

Abstract Hibernation and torpor are not passive responses caused by external temperature drops and fasting but are active brain functions that lower body temperature. A population of neurons in the preoptic area was recently identified as such active torpor-regulating neurons. We hypothesized that the other hypothermia-inducing maneuvers would also activate these neurons. To test our hypothesis, we first refined the previous observations, examined the brain regions explicitly activated during the falling phase of body temperature using c-Fos expression, and confirmed the preoptic area. Next, we observed long-lasting hypothermia by reactivating torpor-tagged Gq-expressing neurons using the activity tagging and DREADD systems. Finally, we found that about 40–60% of torpor-tagged neurons were activated by succeeding isoflurane anesthesia and by icv administration of an adenosine A1 agonist. Isoflurane-induced and central adenosine-induced hypothermia is, at least in part, an active process mediated by the torpor-regulating neurons in the preoptic area. Graphical abstract

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. [ABSTRACT FROM AUTHOR]

Cocaine- and amphetamine- regulated transcript (CART) and Neuropeptide Y (NPY) primarily regulate energy homeostasis. Anurans exhibit diurnal behavioral rhythm, but the response of central neuropeptides to the Day-Night cycle is not elucidated. In this study, we have examined the profile of CART and NPY in the brain of Euphlyctis cyanophlyctis from 6:00 h to 24:00 h. Although expressions of CART and NPY changed with time of the day, circadian oscillation was observed only in expression of CART in anteroventral tegmentum (AV). CART exhibited a single peak in preoptic area (POA), Edinger-Westphal nucleus (EW), nucleus isthmus (NI) and raphe nucleus (Ra); two peaks in ventral hypothamalus (vHy), habenula (Hb) and torus semicircularis (TS). NPY exhibited single peak in TS and suprachiasmatic nucleus (SCN); two peaks in POA, vHy, AV and EW. The daily modulations of these neuropeptides may contribute to their physiological activities and are evolutionarily conserved. [ABSTRACT FROM AUTHOR]

Kisspeptin is an essential neuropeptide sitting at the apex of the hypothalamo-pituitary-gonadal (HPG) endocrine axis to regulate gonadotropin-releasing hormone (GnRH) neurons and downstream reproductive hormones. Kisspeptin neurons integrate feedback from sex steroids facilitating regulation of the menstrual cycle and mediate the effects of metabolic stressors on the reproductive axis. In this issue of the JCI, Torres and colleagues describe another pathway for kisspeptin signaling in astrocytes to influence GnRH neuronal output. Astrocytes had kisspeptin receptors that activated canonical intracellular signaling pathways to constrain the magnitude of kisspeptin-induced GnRH neuronal stimulation. Additionally, the appositions between kisspeptin and GnRH neurons were dynamic during the ovarian cycle, with astrocyte kisspeptin signaling proposed as a putative modulator of this neuroplasticity. Importantly, astrocyte kisspeptin signaling also mediated susceptibility to metabolic stressors and the development of obesity-induced hypogonadism, underscoring the physiological and pathological importance of this pathway and revealing the importance of nonneuronal signaling in reproductive health. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Sexual differentiation of the brain occurs in all major vertebrate lineages but is not well understood at a molecular and cellular level. Unlike most vertebrates, sex-changing fishes have the remarkable ability to change reproductive sex during adulthood in response to social stimuli, offering a unique opportunity to understand mechanisms by which the nervous system can initiate and coordinate sexual differentiation. Methods: This study explores sexual differentiation of the forebrain using single nucleus RNA-sequencing in the anemonefish Amphiprion ocellaris, producing the first cellular atlas of a sex-changing brain. Results: We uncover extensive sex differences in cell type-specific gene expression, relative proportions of cells, baseline neuronal excitation, and predicted inter-neuronal communication. Additionally, we identify the cholecystokinin, galanin, and estrogen systems as central molecular axes of sexual differentiation. Supported by these findings, we propose a model of sexual differentiation in the conserved vertebrate social decision-making network spanning multiple subtypes of neurons and glia, including neuronal subpopulations within the preoptic area that are positioned to regulate gonadal differentiation. Conclusions: This work deepens our understanding of sexual differentiation in the vertebrate brain and defines a rich suite of molecular and cellular pathways that differentiate during adult sex change in anemonefish. Highlights: The first cellular atlas of the forebrain of a sex changing fish. Sex differences in nuclear transcriptomes were observed for multiple different cell types including several different types of glutamate and GABAergic neurons, microglia, radial glia, and oligodendrocytes. Sex differences in the proportion of multiple different types of glutamate neurons, one type of GABAergic neuron and two types of radial glia were observed. Female anemonefish displayed approximately twice as many cholecystokinin-positive/galanin receptor positive glutamate neurons that map to the dorsal medial telencephalon as compared to males. Large sex differences were observed in the proportion of neurons that map to the preoptic area expressing specific sex steroid hormone receptors and neuropeptide receptors, e.g., esr2a, esr2b, cckbr, and pgr. Plain language summary: This study provides key insights into brain sex differences in sex-changing anemonefish (Amphiprion ocellaris), a species that changes sex in adulthood in response to the social environment. Using single nucleus RNA-sequencing, the study provides the first brain cellular atlas showing sex differences in two crucial reproductive areas: the preoptic area and telencephalon. The research identifies notable sex-differences in cell-type proportions and gene expression, particularly in radial glia and glutamatergic neurons that co-express the neuropeptide cholecystokinin. It also highlights differences in preoptic area neurons likely involved in gonadal regulation. This work deepens our understanding of sexual differentiation of the brain in vertebrates, especially those capable of adult sex change, and illuminates key molecular and cellular beginning and endpoints of the process. [ABSTRACT FROM AUTHOR]

Relatively low levels of antioxidant enzymes coupled with high oxygen metabolism result in the formation of numerous oxidative DNA damages in the tissues of the central nervous system. Recently, kynurenic acid (KYNA), knowns for its neuroprotective properties, has gained increasing attention in this context. Therefore, our hypothesis assumed that increased KYNA levels in the brain would positively influence mRNA expression of selected enzymes of the base excision repair pathway as well as enhance their efficiency in excising damaged nucleobases in specific areas of the sheep brain. The study was conducted on adult anestrous sheep (n = 18), in which two different doses of KYNA (20 and 100 μg/day) were infused into the third brain ventricle for three days. Molecular and biochemical analysis included the hypothalamus (preoptic and mediol-basal areas), hippocampus (CA3 field) and amygdala (central amygdaloid nucleus), dissected from the brain of sheep euthanized immediately after the last infusion. The results revealed a significant increase P < 0.001) in the relative mRNA abundance of N-methylpurine DNA glycosylase (MPG) following administration of both dose of KYNA across all examined tissues. The transcription of thymine-DNA glycosylase (TDG) increased significantly (P < 0.001) in all tissues in response to the lower KYNA dose compared to the control group. Moreover, 8-oxoguanine (8-oxoG) DNA glycosylase (OGG1) mRNA levels were also higher in both animal groups (P < 0.001). In addition, in the hypothalamus, hippocampus and amygdala, AP endonuclease 1 (APE1) mRNA expression increased under both doses of KYNA. Moreover, the both dose of KYNA significantly stimulated the efficiency of 8-oxoG excision in hypothalamus and amygdala (P < 0.05–0.001). The lower and higher doses of KYNA significantly influenced the effectiveness of εA and εC in all structures (P < 0.01–0.001). In conclusion, the favorable effect of KYNA in the brain may include the protection of genetic material in nerve and glial cells by stimulating the expression and efficiency of BER pathway enzymes. [ABSTRACT FROM AUTHOR]

It is well known that maternal age at reproduction affects offspring lifespan and some other fitness-related traits, but it remains understudied whether maternal senescence affects how offspring respond to their environments. Early environment often plays a significant role in the development of an animal's behavioral phenotype. For example, complex environments can promote changes in cognitive ability and brain morphology in young animals. Here, we study whether and how maternal effect senescence influences offspring plasticity in cognition, group behavior, and brain morphology in response to environmental complexity. For this, juvenile 3-spined sticklebacks from young and old mothers (i.e. 1-yr and 2-yr-old) were exposed to different levels of environmental enrichment and complexity (i.e. none, simple, and complex), and their behavior, cognitive ability, and brain size were measured. Exposing fish to enriched conditions improved individual learning ability assessed by a repeated detour-reaching task, increased the size of the whole brain, and decreased aggressive interactions in the shoal. Maternal age did not influence the inhibitory control, learning ability, and group behavioral responses of offspring to the experimental environmental change. However, maternal age affected how some brain regions of offspring changed in response to environmental complexity. In offspring from old mothers, those exposed to the complex environment had larger telencephalons and cerebellums than those who experienced simpler environments. Our results suggest that maternal effect senescence may influence how offspring invest in brain functions related to cognition in response to environmental complexity. [ABSTRACT FROM AUTHOR]

Introduction: Owing to their privileged anatomical location, neurons of the arcuate nucleus of the hypothalamus (ARC) play critical roles in sensing and responding to metabolic signals such as leptin and glucagon-like peptide 1 (GLP-1). In addition to the well-known proopiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons, subpopulations of GABAergic neurons are emerging as key regulators of energy balance. However, the precise identity of these metabolic neurons is still elusive. Here, we identified and characterized the molecular signature of a novel population of GABAergic neurons of the ARC expressing Cellular retinoic acid binding protein 1 (Crabp1). Methods: Using a combination of immunohistochemistry and in situ hybridization techniques, we investigated the expression of Crabp1 across the mouse brain and characterized the molecular identity of Crabp1ARC neurons. We also determined whether Crabp1ARC neurons are sensitive to fasting, leptin, and GLP1R agonism by assessing cFOS immunoreactivity as a marker of neuronal activity. Results:Crabp1ARC neurons represent a novel GABAergic neuronal population robustly enriched in the ARC and are distinct from the prototypical melanocortin neurons. Crabp1ARC neurons overlap with three subpopulations of yet uncharacterized ARC neurons expressing Htr3b, Tbx19, and Tmem215. Notably, Crabp1ARC neurons express receptors for metabolic hormones and their activity is modulated by the nutritional state and GLP1R agonism. Conclusion:Crabp1ARC neurons represent a novel heterogeneous population of GABAergic neurons sensitive to metabolic status. [ABSTRACT FROM AUTHOR]

Enkephalins are endogenous opioid pentapeptides that play a role in neurotransmission and pain modulation in vertebrates. However, the distribution pattern of enkephalinergic neurons in the brains of reptiles has been understudied. This study reports the organization of the methionine-enkephalin (M-ENK) and leucine-enkephalin (L-ENK) neuronal systems in the central nervous system of the gecko Hemidactylus frenatus using an immunofluorescence labeling method. Although M-ENK and L-ENK-immunoreactive (ir) fibers extended throughout the pallial and subpallial subdivisions, including the olfactory bulbs, M-ENK and L-ENK-ir cells were found only in the dorsal septal nucleus. Enkephalinergic perikarya and fibers were highly concentrated in the periventricular and lateral preoptic areas, as well as in the anterior and lateral subdivisions of the hypothalamus, while enkephalinergic innervation was observed in the hypothalamic periventricular nucleus, infundibular recess nucleus and median eminence. The dense accumulation of enkephalinergic content was noticed in the pars distalis of the hypophysis. In the thalamus, the nucleus rotundus and the dorsolateral, medial, and medial posterior thalamic nuclei contained M-ENK and L-ENK-ir fibers, whereas clusters of M-ENK and L-ENK-ir neurons were observed in the pretectum, mesencephalon, and rhombencephalon. The enkephalinergic fibers were also seen in the area X around the central canal, as well as the dorsal and ventral horns. The widespread distribution of enkephalin-containing neurons within the central nervous system implies that enkephalins regulate a variety of functions in the gecko, including sensory, behavioral, hypophysiotropic, and neuroendocrine functions. [ABSTRACT FROM AUTHOR]

Growth hormone (GH) receptor (GHR) is abundantly expressed in neurons that co‐release the agouti‐related protein (AgRP) and neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus (ARH). Since ARHAgRP/NPY neurons regulate several hypothalamic–pituitary‐endocrine axes, this neuronal population possibly modulates GH secretion via a negative feedback loop, particularly during food restriction, when ARHAgRP/NPY neurons are highly active. The present study aims to determine the importance of GHR signaling in ARHAgRP/NPY neurons on the pattern of GH secretion in fed and food‐deprived male mice. Additionally, we compared the effect of two distinct situations of food deprivation: 16 h of fasting or four days of food restriction (40% of usual food intake). Overnight fasting strongly suppressed both basal and pulsatile GH secretion. Animals lacking GHR in ARHAgRP/NPY neurons (AgRP∆GHR mice) did not exhibit differences in GH secretion either in the fed or fasted state, compared to control mice. In contrast, four days of food restriction increased GH pulse frequency, basal GH secretion, and pulse irregularity/complexity (measured by sample entropy), whereas pulsatile GH secretion was not affected in both control and AgRP∆GHR mice. Hypothalamic Ghrh mRNA levels were unaffected by fasting or food restriction, but Sst expression increased in acutely fasted mice, but decreased after prolonged food restriction in both control and AgRP∆GHR mice. Our findings indicate that short‐term fasting and prolonged food restriction differentially affect the pattern of GH secretion, independently of GHR signaling in ARHAgRP/NPY neurons. [ABSTRACT FROM AUTHOR]

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

Rapid eye movement sleep (REMs) is characterized by activated electroencephalogram (EEG) and muscle atonia, accompanied by vivid dreams. REMs is homeostatically regulated, ensuring that any loss of REMs is compensated by a subsequent increase in its amount. However, the neural mechanisms underlying the homeostatic control of REMs are largely unknown. Here, we show that GABAergic neurons in the preoptic area of the hypothalamus projecting to the tuberomammillary nucleus (POAGAD2→TMN neurons) are crucial for the homeostatic regulation of REMs in mice. POAGAD2→TMN neurons are most active during REMs, and inhibiting them specifically decreases REMs. REMs restriction leads to an increased number and amplitude of calcium transients in POAGAD2→TMN neurons, reflecting the accumulation of REMs pressure. Inhibiting POAGAD2→TMN neurons during REMs restriction blocked the subsequent rebound of REMs. Our findings reveal a hypothalamic circuit whose activity mirrors the buildup of homeostatic REMs pressure during restriction and that is required for the ensuing rebound in REMs. [ABSTRACT FROM AUTHOR]

Simple Summary: This review aims to discuss the hypothalamic control of hyperthermia in livestock, including the main physiological and behavioral changes that animals adopt to maintain their thermal stability. This review analyzes the main changes that can be observed in livestock when exposed to intense heat. Vasodilation, sweating, and behavioral modifications (e.g., standing posture, shade seeking, feed intake, among others) are the results of neuronal projections from peripheral thermoreceptors to the preoptic area of the hypothalamus and effector neurons. Understanding these mechanisms can help to visualize their effect to restore thermal neutrality in livestock. Hyperthermia elicits several physiological and behavioral responses in livestock to restore thermal neutrality. Among these responses, vasodilation and sweating help to reduce core body temperature by increasing heat dissipation by radiation and evaporation. Thermoregulatory behaviors such as increasing standing time, reducing feed intake, shade-seeking, and limiting locomotor activity also increase heat loss. These mechanisms are elicited by the connection between peripheral thermoreceptors and cerebral centers, such as the preoptic area of the hypothalamus. Considering the importance of this thermoregulatory pathway, this review aims to discuss the hypothalamic control of hyperthermia in livestock, including the main physiological and behavioral changes that animals adopt to maintain their thermal stability. [ABSTRACT FROM AUTHOR]

Aggression is a crucial behavior that impacts access to limited resources in different environmental contexts. Androgens synthesized by the gonads promote aggression during the breeding season. However, aggression can be expressed during the non-breeding season, despite low androgen synthesis by the gonads. The brain can also synthesize steroids ("neurosteroids"), including androgens, which might promote aggression during the non-breeding season. Male song sparrows, Melospiza melodia, are territorial year-round and allow the study of seasonal changes in the steroid modulation of aggression. Here, we quantified steroids following a simulated territorial intrusion (STI) for 10 min in wild adult male song sparrows during the breeding and non-breeding seasons. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we examined 11 steroids: pregnenolone, progesterone, corticosterone, dehydroepiandrosterone, androstenedione, testosterone, 5α-dihydrotestosterone, 17β-estradiol, 17α-estradiol, estriol, and estrone. Steroids were measured in blood and 10 microdissected brain regions that regulate social behavior. In both seasons, STI increased corticosterone in the blood and brain. In the breeding season, STI had no rapid effects on androgens or estrogens. Intriguingly, in the non-breeding season, STI increased testosterone and androstenedione in several behaviorally relevant regions, but not in the blood, where androgens remained non-detectable. Also in the non-breeding season, STI increased progesterone in the blood and specific brain regions. Overall, rapid socially modulated changes in brain steroid levels are more prominent during the non-breeding season. Brain steroid levels vary with season and social context in a region-specific manner and suggest a role for neuroandrogens in aggression during the non-breeding season. [ABSTRACT FROM AUTHOR]

Threat-response neural circuits are conserved across species and play roles in normal behavior and psychiatric diseases. Maladaptive changes in these neural circuits contribute to stress, mood, and anxiety disorders. Active coping in response to stressors is a psychosocial factor associated with resilience against stress-induced mood and anxiety disorders. The neural circuitry underlying active coping is poorly understood, but the functioning of these circuits could be key for overcoming anxiety and related disorders. The supramammillary nucleus (SuM) has been suggested to be engaged by threat. SuM has many projections and a poorly understood diversity of neural populations. In studies using mice, we identified a unique population of glutamatergic SuM neurons (SuMVGLUT2+::POA) based on projection to the preoptic area of the hypothalamus (POA) and found SuMVGLUT2+::POA neurons have extensive arborizations. SuMVGLUT2+::POA neurons project to brain areas that mediate features of the stress and threat responses including the paraventricular nucleus thalamus (PVT), periaqueductal gray (PAG), and habenula (Hb). Thus, SuMVGLUT2+::POA neurons are positioned as a hub, connecting to areas implicated in regulating stress responses. Here we report SuMVGLUT2+::POA neurons are recruited by diverse threatening stressors, and recruitment correlated with active coping behaviors. We found that selective photoactivation of the SuMVGLUT2+::POA population drove aversion but not anxiety like behaviors. Activation of SuMVGLUT2+::POA neurons in the absence of acute stressors evoked active coping like behaviors and drove instrumental behavior. Also, activation of SuMVGLUT2+::POA neurons was sufficient to convert passive coping strategies to active behaviors during acute stress. In contrast, we found activation of GABAergic (VGAT+) SuM neurons (SuMVGAT+) neurons did not alter drive aversion or active coping, but termination of photostimulation was followed by increased mobility in the forced swim test. These findings establish a new node in stress response circuitry that has projections to many brain areas and evokes flexible active coping behaviors. [ABSTRACT FROM AUTHOR]

This study summarizes new data on induced spawning of Steindachneridion parahybae, focusing on the aggressive behavior of females. This study characterizes the vasotocinergic system using immunohistochemistry, highlighting the potential influence of arginine-vasotocin (AVT) on reproductive physiology. Two experimental groups were proposed: (A) control, with one female in the aquarium, and (B) experimental, with two females in the same aquarium. Dominant (D) females presented a more aggressive behavior and did not show any injury. They apparently had a length and body mass higher than injured nondominant (ND) females. The analysis identified positive AVT immunoreactive (ir) neurons exclusively within the preoptic area, including parvocellular, magnocellular, and gigantocellular subpopulations, containing fibers-ir extending into the pituitary gland. Cellular and nuclear areas were greater in D compared to ND in the magnocellular subpopulation. There were no differences between parvocellular and gigantocellular subpopulations. There was a difference on the steroid plasma profile of cortisol (more in ND than in D) and 17α,20β-dihydroxy-4-pregnen-3-one (more in D than in ND). Furthermore, control and D females presented higher optical densities for AVT-ir, gonadotropin-releasing hormone-ir, and luteinizing hormone-ir than ND. In general, there were no differences in the results of female (control group) with D females. The AVT system is highly complex, possibly counting multiple sites of action during artificial reproduction and acting directly and/or indirectly associated with behavioral and physiological changes in S. parahybae females when induced to spawning. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: In nurturing systems, the oxytocin (Oxt)-oxytocin receptor (Oxtr) system is important for parturition, and essential for lactation and parental behavior. Among the nerve nuclei that express Oxtr, the lateral septal nucleus (LS) and medial preoptic area (MPOA) are representative regions that control maternal behavior. Methods: We investigated the role of Oxtr- and Oxtr-expressing neurons, located in the LS and MPOA, in regulating maternal behavior by regulating Oxtr expression in a region-specific manner using recombinant mice and adeno-associated viruses. We quantified the prolactin (Prl) concentrations in the pituitary gland and plasma when Oxtr expression in the MPOA was reduced. Results: The endogenous Oxtr gene in the neurons of the LS did not seem to play an essential role in maternal behavior. Conversely, decreased Oxtr expression in the MPOA increased the frequency of pups being left outside the nest and reduced their survival rate. Deletion of Oxtr in MPOA neurons prevented elevation of Prl levels in plasma and pituitary at postpartum day 2. Discussion/Conclusion: Oxtr-expressing neurons in the MPOA are involved in the postpartum production of Prl. We confirmed the essential functions of Oxtr-expressing neurons and the Oxtr gene itself in the MPOA for the sustainability of maternal behavior, which involved Oxtr-dependent induction of Prl. [ABSTRACT FROM AUTHOR]

Animal welfare has evolved during the past decades to improve not only the quality of life of laboratory rodents but also the quality and reproducibility of scientific investigations. Bibliometric analysis has become an important tool to complete the current knowledge with academic databases. Our objective was to investigate whether scientific research on cannibalism/infanticide is connected with maternal aggression towards the offspring in laboratory rodents. To carry out our research, we performed a specific search for published articles on each concept. Results were analyzed in the open-source environment RStudio with the package Bibliometrix. We obtained 253 and 134 articles for the first search (cannibalism/infanticide) and the second search (maternal aggression towards the pups) respectively. We observed that the interest in infanticide/cannibalism started in the 1950s, while researchers started showing interest in maternal aggression towards the pups 30 years later. Our analyses indicated that maternal aggression had better citations in scientific literature. In addition, although our results showed some common features (e.g. oxytocin or medial preoptic area in the brain), we observed a gap between cannibalism/infanticide and maternal aggression towards the pups with only 14 published articles in common for both the searches. Therefore, we recommend researchers to combine both concepts in further investigations in the context of cannibalism for better dissemination and higher impact in laboratory rodents' welfare research. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article discusses the physiological process of torpor and hibernation in endothermic animals, including mice. Torpor is a hypoactive metabolic state that animals enter during periods of low temperatures and food scarcity to conserve energy. The central nervous system, particularly the hypothalamus, plays a crucial role in regulating torpor. The article presents recent findings on the neural circuits involved in torpor regulation, specifically focusing on the antero-preoptic area, medial preoptic area, and dorsomedial hypothalamus. The article also highlights the need for further research to understand the mechanisms underlying torpor and hibernation in different animal species, including humans. [Extracted from the article]

The ventrolateral preoptic area (VLPO) contains GABAergic sleep-active neurons. However, the extent to which these neurons are involved in expressing spontaneous sleep and homeostatic sleep regulatory demands is not fully understood. We used calcium (Ca2+) imaging to characterize the activity dynamics of VLPO neurons, especially those expressing the vesicular GABA transporter (VGAT) across spontaneous sleep-waking and in response to homeostatic sleep demands. The VLPOs of wild-type and VGAT-Cre mice were transfected with GCaMP6, and the Ca2+ fluorescence of unidentified (UNID) and VGAT cells was recorded during spontaneous sleep-waking and 3 h of sleep deprivation (SD) followed by 1 h of recovery sleep. Although both VGAT and UNID neurons exhibited heterogeneous Ca2+ fluorescence across sleep-waking, the majority of VLPO neurons displayed increased activity during nonREM/REM (VGAT, 120/303; UNID, 39/106) and REM sleep (VGAT, 32/303; UNID, 19/106). Compared to the baseline waking, VLPO sleep-active neurons (n = 91) exhibited higher activity with increasing SD that remained elevated during the recovery period. These neurons also exhibited increased Ca2+ fluorescence during nonREM sleep, marked by increased slow-wave activity and REM sleep during recovery after SD. These findings support the notion that VLPO sleep-active neurons, including GABAergic neurons, are components of neuronal circuitry that mediate spontaneous sleep and homeostatic responses to sustained wakefulness.

The human eye is susceptible to various disorders that affect its structure or function, including glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy (DR). Mitochondrial dysfunction has been identified as a critical factor in the pathogenesis and progression of eye disorders, making it a potential therapeutic target in the clinic. Natural products have been used in traditional medicine for centuries and continue to play a significant role in modern drug development and clinical therapeutics. Recently, there has been a surge in research exploring the efficacy of natural products in treating eye disorders and their underlying physiological mechanisms. This review aims to discuss the involvement of mitochondrial dysfunction in eye disorders and summarize the recent advances in the application of natural products targeting mitochondria. In addition, we describe the future perspective and challenges in the development of mitochondria-targeting natural products. [ABSTRACT FROM AUTHOR]

The posterior intralaminar thalamic nucleus (PIL) and peripeduncular nucleus (PP) are two adjoining structures located medioventral to the medial geniculate nucleus. The PIL-PP region plays important roles in auditory fear conditioning and in social, maternal and sexual behaviors. Previous studies often lumped the PIL and PP into single entity, and therefore it is not known if they have common and/or different brain-wide connections. In this study, we investigate brain-wide efferent and afferent projections of the PIL and PP using reliable anterograde and retrograde tracing methods. Both PIL and PP project strongly to lateral, medial and anterior basomedial amygdaloid nuclei, posteroventral striatum (putamen and external globus pallidus), amygdalostriatal transition area, zona incerta, superior and inferior colliculi, and the ectorhinal cortex. However, the PP rather than the PIL send stronger projections to the hypothalamic regions such as preoptic area/nucleus, anterior hypothalamic nucleus, and ventromedial nucleus of hypothalamus. As for the afferent projections, both PIL and PP receive multimodal information from auditory (inferior colliculus, superior olivary nucleus, nucleus of lateral lemniscus, and association auditory cortex), visual (superior colliculus and ectorhinal cortex), somatosensory (gracile and cuneate nuclei), motor (external globus pallidus), and limbic (central amygdaloid nucleus, hypothalamus, and insular cortex) structures. However, the PP rather than PIL receives strong projections from the visual related structures parabigeminal nucleus and ventral lateral geniculate nucleus. Additional results from Credependent viral tracing in mice have also confirmed the main results in rats. Together, the findings in this study would provide new insights into the neural circuits and functional correlation of the PIL and PP [ABSTRACT FROM AUTHOR]

The natriuretic peptide (NP) family consists of cardiac NPs (ANP, BNP, and VNP) and brain NPs (CNPs) in teleosts. In addition to CNP1-4, a paralogue of CNP4 (named CNP4b) was recently discovered in basal teleosts including Japanese eel. Mammals have lost most Cnps during the evolution, but teleost cnps were conserved and diversified, suggesting that CNPs are important hormones for maintaining brain functions in teleost. The present study evaluated the potency of each Japanese eel CNP to their NP receptors (NPR-A, NPR-B, NPR-C, and NPR-D) overexpressed in CHO cells. A comprehensive brain map of cnps- and nprs-expressing neurons in Japanese eel was constructed by integrating the localization results obtained by in situ hybridization. The result showed that CHO cells expressing NPR-A and NPR-B induced strong cGMP productions after stimulation by cardiac and brain NPs, respectively. Regarding brain distribution of cnps, cnp1 is engaged in the ventral telencephalic area and periventricular area including the parvocellular preoptic nucleus (Pp), anterior/posterior tuberal nuclei, and periventricular gray zone of the optic tectum. cnp3 is found in the habenular nucleus and prolactin cells in the pituitary. cnp4 is expressed in the ventral telencephalic area, while cnp4b is expressed in the motoneurons in the medullary area. Such CNP isoform-specific localizations suggest that function of each CNP has diverged in the eel brain. Furthermore, the Pp lacking the blood-brain barrier expressed both npra and nprb, suggesting that endocrine and paracrine NPs interplay for regulating the Pp functions in Japanese eels. [ABSTRACT FROM AUTHOR]

Aims: The preoptic area (POA) of the hypothalamus, crucial in thermoregulation, has long been implicated in the pain process. However, whether nociceptive stimulation affects body temperature and its mechanism remains poorly studied. Methods: We used capsaicin, formalin, and surgery to induce acute nociceptive stimulation and monitored rectal temperature. Optical fiber recording, chemical genetics, confocal imaging, and pharmacology assays were employed to confirm the role and interaction of POA astrocytes and extracellular adenosine. Immunofluorescence was utilized for further validation. Results: Acute nociception could activate POA astrocytes and induce a decrease in body temperature. Manipulation of astrocytes allowed bidirectional control of body temperature. Furthermore, acute nociception and astrocyte activation led to increased extracellular adenosine concentration within the POA. Activation of adenosine A1 or A2A receptors contributed to decreased body temperature, while inhibition of these receptors mitigated the thermo‐lowering effect of astrocytes. Conclusion: Our results elucidate the interplay between acute nociception and thermoregulation, specifically highlighting POA astrocyte activation. This enriches our understanding of physiological responses to painful stimuli and contributes to the analysis of the anatomical basis involved in the process. [ABSTRACT FROM AUTHOR]

To understand better the role that kisspeptin plays in regulating seasonal and estrous cycle changes in the mare, this study investigated the number, location and interactions between GnRH, kisspeptin and RFRP-3 neurons in the equine hypothalamus. Hypothalami were collected from mares during the non-breeding season, vernal transition and various stages of the breeding season. Fluorescent immunohistochemistry was used to label the neuropeptides of interest. GnRH cells were observed primarily in the arcuate nucleus (ARC), while very few labeled cells were identified in the pre-optic area (POA). Kisspeptin cells were identified primarily in the ARC, with a small number of cells observed dorsal to the ARC, surrounding the third ventricle (3V). The mean number of kisspeptin cells varied between animals and typically showed no pattern associated with season or stage of estrous cycle, but a seasonal difference was identified in the ARC population. Small numbers of RFRP-3 cells were observed in the ARC, ventromedial hypothalamus (VMH) and dorsomedial hypothalamus (DMH). The mean number of RFRP-3 cells appeared higher in pre-ovulatory animals compared to all other stages. The percentage of GnRH cell bodies with kisspeptin appositions did not change with season or stage of estrous cycle. The percentage of kisspeptin cells receiving inputs from RFRP-3 fibers did not vary with season or stage of estrous cycle. These interactions suggest the possibility of the presence of an ultra-short loop feedback system between these three peptides. The changes in RFRP-3 neurons suggest the possibility of a role in the regulation of reproduction in the horse, but it is unlikely to be as a gonadotropin inhibitory factor. • Study investigated the number, location and interactions between GnRH, kisspeptin and RFRP-3 neurons in the hypothalamus of the mare. • Compared numbers across the estrous cycle and between seasons. [ABSTRACT FROM AUTHOR]

Nest-building behavior is a widely observed innate behavior. A nest provides animals with a secure environment for parenting, sleep, feeding, reproduction, and temperature maintenance. Since animal infants spend their time in a nest, nest-building behavior has been generally studied as parental behaviors, and the medial preoptic area (MPOA) neurons are known to be involved in parental nest-building. However, nest-building of singly housed male mice has been less examined. Here we show that male mice spent longer time in nest-building at the early to middle dark phase and at the end of the dark phase. These two periods are followed by sleep-rich periods. When a nest was removed and fresh nest material was introduced, both male and female mice built nests at Zeitgeber time (ZT) 6, but not at ZT12. Using Fos-immunostaining combined with double in situ hybridization of Vgat and Vglut2, we found that Vgat- and Vglut2-positive cells of the lateral preoptic area (LPOA) were the only hypothalamic neuron population that exhibited a greater number of activated cells in response to fresh nest material at ZT6, compared to being naturally awake at ZT12. Fos-positive LPOA neurons were negative for estrogen receptor 1 (Esr1). Both Vgat-positive and Vglut2-positive neurons in both the LPOA and MPOA were activated at pup retrieval by male mice. Our findings suggest the possibility that GABAergic and glutamatergic neurons in the LPOA are associated with nest-building behavior in male mice. [ABSTRACT FROM AUTHOR]

Animals need sleep, and the suprachiasmatic nucleus, the center of the circadian rhythm, plays an important role in determining the timing of sleep. The main input to the suprachiasmatic nucleus is the retinohypothalamic tract, with additional inputs from the intergeniculate leaflet pathway, the serotonergic afferent from the raphe, and other hypothalamic regions. Within the suprachiasmatic nucleus, two of the major subtypes are vasoactive intestinal polypeptide (VIP)-positive neurons and arginine-vasopressin (AVP)-positive neurons. VIP neurons are important for light entrainment and synchronization of suprachiasmatic nucleus neurons, whereas AVP neurons are important for circadian period determination. Output targets of the suprachiasmatic nucleus include the hypothalamus (subparaventricular zone, paraventricular hypothalamic nucleus, preoptic area, and medial hypothalamus), the thalamus (paraventricular thalamic nuclei), and lateral septum. The suprachiasmatic nucleus also sends information through several brain regions to the pineal gland. The olfactory bulb is thought to be able to generate a circadian rhythm without the suprachiasmatic nucleus. Some reports indicate that circadian rhythms of the olfactory bulb and olfactory cortex exist in the absence of the suprachiasmatic nucleus, but another report claims the influence of the suprachiasmatic nucleus. The regulation of circadian rhythms by sensory inputs other than light stimuli, including olfaction, has not been well studied and further progress is expected. [ABSTRACT FROM AUTHOR]

The adipocyte-derived hormone, leptin, plays a key role in the maintenance of energy homeostasis. Leptin binds to the long form of its receptor, which is predominantly expressed in various hypothalamic regions, including the lateral hypothalamic area (LH) and supraoptic nucleus (SO). Several studies have suggested that leptin directly activates neuronal nitric oxide synthase, leading to increased nitric oxide production. We used histochemistry for nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) as a marker for nitric oxide synthase activity and assessed the effect of leptin on nitrergic neurons in the LH and SO of rats. We found that intraperitoneal administration of leptin led to a significant increase in the number of NADPH-d-positive neurons in the LH and SO. In addition, the intensity (optical density) of NADPH-d staining in LH and SO neurons was significantly elevated in rats that received leptin compared with saline-treated rats. These findings suggest that nitrergic neurons in the LH and SO may be implicated in mediating the central effects of leptin. [ABSTRACT FROM AUTHOR]

Aims To examine the influence of GED on the gut microbiota and metabolites using a bilateral ovariectomized (OVX) rat model. We tried to elucidate the underlying mechanisms of GED in the treatment of menopausal hot flashes. Methods and results 16S rRNA sequencing, metabonomics, molecular biological analysis, and fecal microbiota transplantation (FMT) were conducted to elucidate the mechanisms by which GED regulates the gut microbiota. GED significantly reduced OVX-induced hot flashes and improved disturbances in the gut microbiota metabolites. Moreover, FMT validated that the gut microbiota can trigger hot flashes, while GED can alleviate hot flash symptoms by modulating the composition of the gut microbiota. Specifically, GED upregulated the abundance of Blautia , thereby increasing l (+)-ornithine levels for the treatment of menopausal hot flashes. Additionally, GED affected endothelial nitric oxide synthase and heat shock protein 70 (HSP70) levels in the hypothalamic preoptic area by changing the gut microbiota composition. Conclusions Our study illuminated the underlying mechanisms by which GED attenuated the hot flashes through modulation of the gut microbiota and explored the regulatory role of the gut microbiota on HSP70 expression in the preoptic anterior hypothalamus, thereby establishing a foundation for further exploration of the role of the gut–brain axis in hot flashes. [ABSTRACT FROM AUTHOR]

The vertebrate telencephalic lobes consist of the pallium (dorsal) and subpallium (ventral). The subpallium gives rise to the basal ganglia, encompassing the pallidum and striatum. The development of this region is believed to depend on Foxg1/Foxg1a functions in both mice and zebrafish. This study aims to elucidate the genetic regulatory network controlled by foxg1a in subpallium development using zebrafish as a model. The expression gradient of foxg1a within the developing telencephalon was examined semi‐quantitatively in initial investigations. Utilizing the CRISPR/Cas9 technique, we subsequently established a foxg1a mutant line and observed the resultant phenotypes. Morphological assessment revealed that foxg1a mutants exhibit a thin telencephalon together with a misshapen preoptic area (POA). Notably, accumulation of apoptotic cells was identified in this region. In mutants at 24 h postfertilization, the expression of pallium markers expanded ventrally, while that of subpallium markers was markedly suppressed. Concurrently, the expression of fgf8a, vax2, and six3b was shifted ventrally, causing anomalous expression in regions typical of POA formation in wild‐type embryos. Consequently, the foxg1a mutation led to expansion of the pallium and disrupted the subpallium and POA. This highlights a pivotal role of foxg1a in directing the dorsoventral patterning of the telencephalon, particularly in subpallium differentiation, mirroring observations in mice. Additionally, reduced expression of neural progenitor maintenance genes was detected in mutants, suggesting the necessity of foxg1a in preserving neural progenitors. Collectively, these findings underscore evolutionarily conserved functions of foxg1 in the development of the subpallium in vertebrate embryos. [ABSTRACT FROM AUTHOR]