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Neuroanatomy and heterogeneity of the medial preoptic area. (A) Coronal mouse brain diagram showing the MPOA subregions at the level of the MPNc (bregma, –0.02 mm). (B) Double ISH for Penk (blue) and neurotensin (magenta) mRNAs with immunostaining for calbindin (green). (C) ISH for Vglut2 (green) mRNA with immunostaining for oxytocin (magenta). (D) Summary of marker genes expression in selected MPOA subregions. Each subregion has a characteristic pattern of marker expression. Scale bars: 100 μm. 3v, third ventricle; ac, anterior commissure; ACN, anterior commissural nucleus; BNSTdm, dorsomedial nucleus of the BNST; BNSTmg, magnocellular nucleus of the BNST; cMPOA, central part of the MPOA; dmMPOA, dorsomedial part of the MPOA; MPNc, central part of the MPN; MPNl, lateral part of the MPN; MPNmp, posteromedial part of the MPN; MPNvl, ventrolateral part of the MPN; opt, optic tract; PD, posterodorsal preoptic nucleus; vMPOA, ventral part of the MPOA; vlMPOA, ventrolateral part of the MPOA; VLPO, ventrolateral preoptic nucleus. Modified from Tsuneoka et al. (2017b).
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The preoptic area (POA) has long been recognized as a sleep center, first proposed by von Economo. The POA, especially the medial POA (MPOA), is also involved in the regulation of various innate functions such as sexual and parental behaviors. Consistent with its many roles, the MPOA is composed of subregions that are identified by different gene a...
Citations
... Since the hypothalamus is involved in the regulation of behaviors closely related to nest-building, such as warmsensing, sleep/wakefulness, and parenting [8][9][10][11]17 , we examined which hypothalamic areas have more neurons that are activated in response to fresh nest material. We harvested brains 120 min after providing fresh nest material www.nature.com/scientificreports/ to singly housed male mice at ZT6 and performed c-Fos immunostaining. ...
... Nest-building has been well studied as a maternal behavior in female mice and the POA has been reported to be involved in parental behavior 7,9,13 . Mating and cohabitation with female induce paternal behavior of male mice, whereas virgin male mice exhibit aggressive behavior to pups 18 www.nature.com/scientificreports/ ...
... Reflecting differences in their involvement in nest-building behavior, the MPOA and LPOA are adjacent but differ in gene expression 9 . For example, galanin, neurotensin, and estrogen receptor genes are rich in the MPOA but devoid in the LPOA. ...
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.
... Adenosine binds to receptors on VLPO neurons, enhancing GABAergic transmission. The inhibitory actions of GABA released from the VLPO contribute to the dampening of arousal-promoting circuits, facilitating the transition to sleep [35][36][37]. ...
The relationship between sleep, glial cells, and the endocannabinoid system represents a multifaceted regulatory network with profound implications for neuroinflammation and cognitive function. The molecular underpinnings of sleep modulation by the endocannabinoid system and its influence on glial cell activity are discussed, shedding light on the reciprocal relationships that govern these processes. Emphasis is placed on understanding the role of glial cells in mediating neuroinflammatory responses and their modulation by sleep patterns. Additionally, this review examines how the endocannabinoid system interfaces with glia-immune signaling to regulate inflam-matory cascades within the central nervous system. Notably, the cognitive consequences of disrupted sleep, neuroinflammation, and glial dysfunction are addressed, encompassing implications for neu-rodegenerative disorders, mood disturbances, and cognitive decline. Insights into the bidirectional modulation of cognitive function by the endocannabinoid system in the context of sleep and glial activity are explored, providing a comprehensive perspective on the potential mechanisms underlying cognitive impairments associated with sleep disturbances. Furthermore, this review examines potential therapeutic avenues targeting the endocannabinoid system to mitigate neuroinflammation, restore glial homeostasis, and normalize sleep patterns. The identification of novel therapeutic targets within this intricate regulatory network holds promise for addressing conditions characterized by disrupted sleep, neuroinflammation, and cognitive dysfunction. This work aims to examine the complexities of neural regulation and identify potential avenues for therapeutic intervention.
... According to Simerly, the MPOA is one of the 12 (3 × 4, in mediolateral and rostrocaudal) divisions of the preoptichypothalamic continuum ( Figure 1A). 31 The MPOA contains multiple subnuclei segregated by distinct cellular morphologies, molecular expression patterns, connectivity, and biological functions, [31][32][33][34][35] such as sleep at the ventrolateral preoptic nucleus (VLPO), 36,37 thermo-and osmoregulation at the median preoptic nucleus (MnPO), 38,39 puberty onset and fertility through kisspeptin and gonadotropin-releasing hormone (GnRH) neurons located in the anteroventral preoptic area (AVPV) and ventral part of the MPOA, 40 and male sexual behaviors at the medial preoptic nucleus (MPN). [41][42][43][44] The MPN is also implicated in proceptive/appetitive components of female sexual behaviors, though dispensable for the consummatory lordosis component. ...
This review consolidates current knowledge on mammalian parental care, focusing on its neural mechanisms, evolutionary origins, and derivatives. Neurobiological studies have identified specific neurons in the medial preoptic area as crucial for parental care. Unexpectedly, these neurons are characterized by the expression of molecules signaling satiety, such as calcitonin receptor and BRS3, and overlap with neurons involved in the reproductive behaviors of males but not females. A synthesis of comparative ecology and paleontology suggests an evolutionary scenario for mammalian parental care, possibly stemming from male‐biased guarding of offspring in basal vertebrates. The terrestrial transition of tetrapods led to prolonged egg retention in females and the emergence of amniotes, skewing care toward females. The nocturnal adaptation of Mesozoic mammalian ancestors reinforced maternal care for lactation and thermal regulation via endothermy, potentially introducing metabolic gate control in parenting neurons. The established maternal care may have served as the precursor for paternal and cooperative care in mammals and also fostered the development of group living, which may have further contributed to the emergence of empathy and altruism. These evolution‐informed working hypotheses require empirical validation, yet they offer promising avenues to investigate the neural underpinnings of mammalian social behaviors.
... The MPOA plays a critical role in both parenting and sexual behaviors, as well as in the regulation of essential physiological functions such as body temperature control, thirst, and sleep (Zimmerman et al., 2017;Tan and Knight, 2018;Tsuneoka and Funato, 2021). The neural circuits governing these functions are likely to be composed of neurons with distinct genetic identities. ...
Parental care plays a crucial role in the physical and mental well-being of mammalian offspring. Although sexually naïve male mice, as well as certain strains of female mice, display aggression toward pups, they exhibit heightened parental caregiving behaviors as they approach the time of anticipating their offspring. In this Mini Review, I provide a concise overview of the current understanding of distinct limbic neural types and their circuits governing both aggressive and caregiving behaviors toward infant mice. Subsequently, I delve into recent advancements in the understanding of the molecular, cellular, and neural circuit mechanisms that regulate behavioral plasticity during the transition to parenthood, with a specific focus on the sex steroid hormone estrogen and neural hormone oxytocin. Additionally, I explore potential sex-related differences and highlight some critical unanswered questions that warrant further investigation.
... The hypothalamus was the only major division found to be differentially active under steady-state isoflurane in males and females (P = 0.0059, permutation test) (SI Appendix, Table S5). Sexually dimorphic hypothalamic structures are located throughout the greater preoptic area (15,16,78), which is also known to modulate arousal both during natural sleep (79,80) and anesthetic-induced unconsciousness (Fig. 4) (2,11,81). Compared to females, areas with significantly greater c-Fos expression levels in males included the ventrolateral preoptic, retrochiasmatic area (partially overlapping with the supraoptic nucleus), median preoptic (including the vascular organ of the lamina terminalis), medial preoptic, lateral preoptic, and paraventricular hypothalamic nuclei (for a full list, see SI Appendix, Table S4). ...
General anesthesia—a pharmacologically induced reversible state of unconsciousness—enables millions of life-saving procedures. Anesthetics induce unconsciousness in part by impinging upon sexually dimorphic and hormonally sensitive hypothalamic circuits regulating sleep and wakefulness. Thus, we hypothesized that anesthetic sensitivity should be sex-dependent and modulated by sex hormones. Using distinct behavioral measures, we show that at identical brain anesthetic concentrations, female mice are more resistant to volatile anesthetics than males. Anesthetic sensitivity is bidirectionally modulated by testosterone. Castration increases anesthetic resistance. Conversely, testosterone administration acutely increases anesthetic sensitivity. Conversion of testosterone to estradiol by aromatase is partially responsible for this effect. In contrast, oophorectomy has no effect. To identify the neuronal circuits underlying sex differences, we performed whole brain c-Fos activity mapping under anesthesia in male and female mice. Consistent with a key role of the hypothalamus, we found fewer active neurons in the ventral hypothalamic sleep-promoting regions in females than in males. In humans, we demonstrate that females regain consciousness and recover cognition faster than males after identical anesthetic exposures. Remarkably, while behavioral and neurocognitive measures in mice and humans point to increased anesthetic resistance in females, cortical activity fails to show sex differences under anesthesia in either species. Cumulatively, we demonstrate that sex differences in anesthetic sensitivity are evolutionarily conserved and not reflected in conventional electroencephalographic-based measures of anesthetic depth. This covert resistance to anesthesia may explain the higher incidence of unintended awareness under general anesthesia in females.
... The medial preoptic area (MPOA), a molecularly and functionally heterogenous brain region, has classically been known to regulate wide variety of social behaviors (Fang et al., 2018 ;Hashikawa et al., 2021 ;Karigo et al., 2021 ;Kohl et al., 2018 ;Moffitt et al., 2018 ;Tsuneoka and Funato, 2021 ;Wei et al., 2018 ). Indeed, the MPOA has also been described to be an important brain area for the regulation of, including female sexual behavior. ...
... We further demonstrate that the inhibitory population contains neurons that show prolonged responses to mating completion which resemble the persistent change of sexual motivation. Other studies have also supported the idea that the inhibitory cell population is more related to the regulation of social behavior than the excitatory population (Fang et al., 2018 ;Hashikawa et al., 2021 ;Moffitt et al., 2018 ;Tsuneoka and Funato, 2021 ;G.-W. Zhang et al., 2021 ). ...
The completion of mating acutely suppresses sexual motivation in male mice. In contrast, relatively little is known about how the completion of mating affects sexual motivation and sexual behavior in female mice. How the brain responds to completion of mating is also unclear. Here, by using self-paced mating assay, we first demonstrate that female mice show decreased sexual motivation after the completion of mating. By using brain-wide analysis of activity-dependent labeling, we next pin-pointed the medial preoptic area as a brain region strongly responding to mating completion. Furthermore, using freely moving in vivo calcium imaging to compare neural activity of inhibitory and excitatory neurons in the medial preoptic area, we revealed that a subset of neurons responds significantly and specifically to mating completion but not to appetitive or consummatory behaviors. While there were excitatory and inhibitory neurons that showed positive response to the completion of mating, the response magnitude as well as the proportion of neurons responding to the event was significantly larger in the inhibitory neuron population. Next, by unbiased classification of their responses, we also found a subpopulation of neurons that increase their activity late after the onset of the completion of mating. These neurons were all inhibitory indicating that the completion of mating induces a prolonged inhibitory activity in the medial preoptic area. Lastly, we found that chemogenetic activation of medial preoptic area neurons that respond to mating completion, but not to appetitive behaviors, was sufficient to suppress female sexual motivation. Together, our data illuminate the importance of medial preoptic area as a brain node which encodes a negative signal that sustains low sexual motivation state after the completion of mating in female mice.
Female mice show decreased sexual motivation after mating completion.
A subset of MPOA neurons respond specifically to mating completion.
Mating completion evokes persistent activity in MPOA inhibitory neurons.
Activation of a subset of MPOA neurons is sufficient to suppress female sexual motivation.
... Hypothalamic POA serves as an essential brain region in maintaining and regulating body temperature [28][29][30][31] . As a multifunctional region, POA can be divided into several nuclei and is composed of different types of neurons to form complex neural circuits and modulate body temperature, sleep, feeding, sexual behavior, and so on 28,56 . In our study, we identify that POA may be the key brain target region of P57 to induce hypothermia. ...
... Further study combing TRAP mouse line 59 and optogenetic/chemogenetic tools may help us dissect the specific MPA neuron and neural circuit involved in the P57-induced hypothermia. In addition to thermoregulation, POA is also involved in regulating sleep and feeding behavior 28,56,60,61 . P57 is well-known for its prominent activity in appetite suppression with undefined mechanism 39,40 , so P57 may also target POA to regulate feeding behavior and sleep. ...
Induction of hypothermia during hibernation/torpor enables certain mammals to survive under extreme environmental conditions. However, pharmacological induction of hypothermia in most mammals remains a huge challenge. Here we show that a natural product P57 promptly induces hypothermia and decreases energy expenditure in mice. Mechanistically, P57 inhibits the kinase activity of pyridoxal kinase (PDXK), a key metabolic enzyme of vitamin B6 catalyzing phosphorylation of pyridoxal (PL), resulting in the accumulation of PL in hypothalamus to cause hypothermia. The hypothermia induced by P57 is significantly blunted in the mice with knockout of PDXK in the preoptic area (POA) of hypothalamus. We further found that P57 and PL have consistent effects on gene expression regulation in hypothalamus, and they may activate medial preoptic area (MPA) neurons in POA to induce hypothermia. Taken together, our findings demonstrate that P57 has a potential application in therapeutic hypothermia through regulation of vitamin B6 metabolism and PDXK serves as a previously unknown target of P57 in thermoregulation. In addition, P57 may serve as a chemical probe for exploring the neuron circuitry related to hypothermia state in mice.
... These nuclei have distinct cell types (i.e., cholinergic and parvalbumin neurons, respectively [66]), suggesting that poor performance in avoidance behavior involves a dysregulation in the habenular complex. Moreover, both structures receive inputs from the magnocellular preoptic nucleus, which has an important role in neuroendocrine responses [67]. Notably, while good and poor performers showed a decrease in astroglial IR in the LHbLB, only poor performers showed an increase in the neuronal activation pattern. ...
Understanding the mechanisms responsible for anxiety disorders is a major challenge. Avoidance behavior is an essential feature of anxiety disorders. The two-way avoidance test is a preclinical model with two distinct subpopulations—the good and poor performers—based on the number of avoidance responses presented during testing. It is believed that the habenula subnuclei could be important for the elaboration of avoidance response with a distinct pattern of activation and neuroinflammation. The present study aimed to shed light on the habenula subnuclei signature in avoidance behavior, evaluating the pattern of neuronal activation using FOS expression and astrocyte density using GFAP immunoreactivity, and comparing control, good and poor performers. Our results showed that good performers had a decrease in FOS immunoreactivity (IR) in the superior part of the medial division of habenula (MHbS) and an increase in the marginal part of the lateral subdivision of lateral habenula (LHbLMg). Poor performers showed an increase in FOS in the basal part of the lateral subdivision of lateral habenula (LHbLB). Considering the astroglial immunoreactivity, the poor performers showed an increase in GFAP-IR in the inferior portion of the medial complex (MHbl), while the good performers showed a decrease in the oval part of the lateral part of the lateral complex (LHbLO) in comparison with the other groups. Taken together, our data suggest that specific subdivisions of the MHb and LHb have different activation patterns and astroglial immunoreactivity in good and poor performers. This study could contribute to understanding the neurobiological mechanisms responsible for anxiety disorders.
... Multiple lines of studies support the notion that the ventrolateral preoptic area (VLPO) is involved in the regulation of a broad repertoire of vital functions, including thermoregulation, sexual behavior, and sleep [1][2][3][4][5][6] VLPO lesions result in significant sleep fragmentation and insomnia or decreased sleep [7]. The VLPO contains a high density of sleep-active neurons or neurons that exhibit increasing discharge from waking → non-rapid eye movement (nonREM) sleep transition → stable nonREM/REM sleep, indicating that these neurons are involved in the initiation/maintenance of sleep [8,9]. ...
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.
... Neurons in and around the ventrolateral preoptic nucleus (VLPO) in the POA are known to play a significant role in sleep regulation (Tsuneoka and Funato, 2021). These neurons send GABAergic projections to wakefulness-promoting neuronal populations (Weber and Dan, 2016;Scammell et al., 2017). ...
To understand how sleep-wakefulness cycles are regulated, it is essential to disentangle structural and functional relationships between the preoptic area (POA) and lateral hypothalamic area (LHA), since these regions play important yet opposing roles in the sleep-wakefulness regulation. GABA- and galanin (GAL)-producing neurons in the ventrolateral preoptic nucleus (VLPO) of the POA (VLPO GABA and VLPO GAL neurons) are responsible for the maintenance of sleep, while the LHA contains orexin-producing neurons (orexin neurons) that are crucial for maintenance of wakefulness. Through the use of rabies virus-mediated neural tracing combined with in situ hybridization in male and female orexin-iCre mice, we revealed that the vesicular GABA transporter ( Vgat, Slc32a1 )- and galanin ( Gal )-expressing neurons in the VLPO directly synapse with orexin neurons in the LHA. A majority (56.3±8%) of all VLPO input neurons connecting to orexin neurons were double-positive for Vgat and Gal . Using projection-specific rabies virus-mediated tracing in male and female Vgat-ires-Cre and Gal-Cre mice, we discovered that VLPO GABA and VLPO GAL neurons that send projections to the LHA received innervations from similarly distributed input neurons in many brain regions, with the POA and LHA being among the main upstream areas. Additionally, we found that acute optogenetic excitation of axons of VLPO GABA neurons, but not VLPO GAL neurons, in the LHA of male Vgat-ires-Cre mice induced wakefulness. This study deciphers the connectivity between the VLPO and LHA, provides a large-scale map of upstream neuronal populations of VLPO→LHA neurons, and reveals a previously uncovered function of the VLPO GABA →LHA pathway in the regulation of sleep and wakefulness.
Significance statement:
We identified that neurons in the VLPO, that are positive for vesicular GABA transporter ( Vgat )- and/or galanin ( Gal ), serve as presynaptic partners of orexin-producing neurons in the LHA. We depicted monosynaptic input neurons of GABA- and galanin-producing neurons in the VLPO that send projections to the LHA throughout the entire brain. Their input neurons largely overlap, suggesting that they comprise a common neuronal population. However, acute excitatory optogenetic manipulation of VLPO GABA →LHA pathway, but not VLPO GAL →LHA pathway, evoked wakefulness. This study shows the connectivity of major components of the sleep/wake circuitry in the hypothalamus and unveils a previously unrecognized function of the VLPO GABA →LHA pathway in sleep-wakefulness regulation. Furthermore, we suggest the existence of subpopulations of VLPO GABA neurons that innervate LHA.
