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Science (New York, N.Y.) Nov 2018The hypothalamus controls essential social behaviors and homeostatic functions. However, the cellular architecture of hypothalamic nuclei-including the molecular...
The hypothalamus controls essential social behaviors and homeostatic functions. However, the cellular architecture of hypothalamic nuclei-including the molecular identity, spatial organization, and function of distinct cell types-is poorly understood. Here, we developed an imaging-based in situ cell-type identification and mapping method and combined it with single-cell RNA-sequencing to create a molecularly annotated and spatially resolved cell atlas of the mouse hypothalamic preoptic region. We profiled ~1 million cells, identified ~70 neuronal populations characterized by distinct neuromodulatory signatures and spatial organizations, and defined specific neuronal populations activated during social behaviors in male and female mice, providing a high-resolution framework for mechanistic investigation of behavior circuits. The approach described opens a new avenue for the construction of cell atlases in diverse tissues and organisms.
Topics: Animals; Atlases as Topic; Female; Galanin; Gene Expression Profiling; In Situ Hybridization, Fluorescence; Male; Mice; Neurons; Pituitary Adenylate Cyclase-Activating Polypeptide; Preoptic Area; Sequence Analysis, RNA; Single-Cell Analysis; Social Behavior
PubMed: 30385464
DOI: 10.1126/science.aau5324 -
Science (New York, N.Y.) Oct 2023During pregnancy, physiological adaptations prepare the female body for the challenges of motherhood. Becoming a parent also requires behavioral adaptations. Such...
During pregnancy, physiological adaptations prepare the female body for the challenges of motherhood. Becoming a parent also requires behavioral adaptations. Such adaptations can occur as early as during pregnancy, but how pregnancy hormones remodel parenting circuits to instruct preparatory behavioral changes remains unknown. We found that action of estradiol and progesterone on galanin (Gal)-expressing neurons in the mouse medial preoptic area (MPOA) is critical for pregnancy-induced parental behavior. Whereas estradiol silences MPOA neurons and paradoxically increases their excitability, progesterone permanently rewires this circuit node by promoting dendritic spine formation and recruitment of excitatory synaptic inputs. This MPOA-specific neural remodeling sparsens population activity in vivo and results in persistently stronger, more selective responses to pup stimuli. Pregnancy hormones thus remodel parenting circuits in anticipation of future behavioral need.
Topics: Animals; Female; Mice; Pregnancy; Estradiol; Maternal Behavior; Parenting; Preoptic Area; Progesterone; Models, Animal; Neurons
PubMed: 37797007
DOI: 10.1126/science.adi0576 -
Nature Neuroscience Apr 2021Anxiety is a negative emotional state that is overly displayed in anxiety disorders and depression. Although anxiety is known to be controlled by distributed brain...
Anxiety is a negative emotional state that is overly displayed in anxiety disorders and depression. Although anxiety is known to be controlled by distributed brain networks, key components for its initiation, maintenance and coordination with behavioral state remain poorly understood. Here, we report that anxiogenic stressors elicit acute and prolonged responses in glutamatergic neurons of the mouse medial preoptic area (mPOA). These neurons encode extremely negative valence and mediate the induction and expression of anxiety-like behaviors. Conversely, mPOA GABA-containing neurons encode positive valence and produce anxiolytic effects. Such opposing roles are mediated by competing local interactions and long-range projections of neurons to the periaqueductal gray. The two neuronal populations antagonistically regulate anxiety-like and parental behaviors: anxiety is reduced, while parenting is enhanced and vice versa. Thus, by evaluating negative and positive valences through distinct but interacting circuits, the mPOA coordinates emotional state and social behavior.
Topics: Animals; Anxiety; Behavior, Animal; Female; GABAergic Neurons; Glutamine; Male; Mice; Mice, Inbred C57BL; Neurons; Preoptic Area; Social Behavior; Stress, Psychological
PubMed: 33526942
DOI: 10.1038/s41593-020-00784-3 -
Nature Jun 2022During infection, animals exhibit adaptive changes in physiology and behaviour aimed at increasing survival. Although many causes of infection exist, they trigger...
During infection, animals exhibit adaptive changes in physiology and behaviour aimed at increasing survival. Although many causes of infection exist, they trigger similar stereotyped symptoms such as fever, warmth-seeking, loss of appetite and fatigue. Yet exactly how the nervous system alters body temperature and triggers sickness behaviours to coordinate responses to infection remains unknown. Here we identify a previously uncharacterized population of neurons in the ventral medial preoptic area (VMPO) of the hypothalamus that are activated after sickness induced by lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid. These neurons are crucial for generating a fever response and other sickness symptoms such as warmth-seeking and loss of appetite. Single-nucleus RNA-sequencing and multiplexed error-robust fluorescence in situ hybridization uncovered the identity and distribution of LPS-activated VMPO (VMPO) neurons and non-neuronal cells. Gene expression and electrophysiological measurements implicate a paracrine mechanism in which the release of immune signals by non-neuronal cells during infection activates nearby VMPO neurons. Finally, we show that VMPO neurons exert a broad influence on the activity of brain areas associated with behavioural and homeostatic functions and are synaptically and functionally connected to circuit nodes controlling body temperature and appetite. Together, these results uncover VMPO neurons as a control hub that integrates immune signals to orchestrate multiple sickness symptoms in response to infection.
Topics: Animals; Appetite; Appetite Depressants; Fever; In Situ Hybridization, Fluorescence; Infections; Lipopolysaccharides; Neurons; Paracrine Communication; Poly I-C; Preoptic Area
PubMed: 35676482
DOI: 10.1038/s41586-022-04793-z -
Science (New York, N.Y.) Sep 2017Water deprivation produces a drive to seek and consume water. How neural activity creates this motivation remains poorly understood. We used activity-dependent genetic...
Water deprivation produces a drive to seek and consume water. How neural activity creates this motivation remains poorly understood. We used activity-dependent genetic labeling to characterize neurons activated by water deprivation in the hypothalamic median preoptic nucleus (MnPO). Single-cell transcriptional profiling revealed that dehydration-activated MnPO neurons consist of a single excitatory cell type. After optogenetic activation of these neurons, mice drank water and performed an operant lever-pressing task for water reward with rates that scaled with stimulation frequency. This stimulation was aversive, and instrumentally pausing stimulation could reinforce lever-pressing. Activity of these neurons gradually decreased over the course of an operant session. Thus, the activity of dehydration-activated MnPO neurons establishes a scalable, persistent, and aversive internal state that dynamically controls thirst-motivated behavior.
Topics: Animals; Cell Line; Dehydration; Drinking Behavior; Gene Expression Profiling; Mice; Motivation; Neurons; Optogenetics; Preoptic Area; Single-Cell Analysis; TNF Receptor-Associated Factor 2; Thirst
PubMed: 28912243
DOI: 10.1126/science.aan6747 -
Nature Sep 2021Transient neuromodulation can have long-lasting effects on neural circuits and motivational states. Here we examine the dopaminergic mechanisms that underlie mating...
Transient neuromodulation can have long-lasting effects on neural circuits and motivational states. Here we examine the dopaminergic mechanisms that underlie mating drive and its persistence in male mice. Brief investigation of females primes a male's interest to mate for tens of minutes, whereas a single successful mating triggers satiety that gradually recovers over days. We found that both processes are controlled by specialized anteroventral and preoptic periventricular (AVPV/PVpo) dopamine neurons in the hypothalamus. During the investigation of females, dopamine is transiently released in the medial preoptic area (MPOA)-an area that is critical for mating behaviours. Optogenetic stimulation of AVPV/PVpo dopamine axons in the MPOA recapitulates the priming effect of exposure to a female. Using optical and molecular methods for tracking and manipulating intracellular signalling, we show that this priming effect emerges from the accumulation of mating-related dopamine signals in the MPOA through the accrual of cyclic adenosine monophosphate levels and protein kinase A activity. Dopamine transients in the MPOA are abolished after a successful mating, which is likely to ensure abstinence. Consistent with this idea, the inhibition of AVPV/PVpo dopamine neurons selectively demotivates mating, whereas stimulating these neurons restores the motivation to mate after sexual satiety. We therefore conclude that the accumulation or suppression of signals from specialized dopamine neurons regulates mating behaviours across minutes and days.
Topics: Animals; Copulation; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dopamine; Dopaminergic Neurons; Drive; Female; Hypothalamus; Male; Mice; Optogenetics; Preoptic Area; Satiety Response; Sexual Behavior, Animal; Signal Transduction; Time Factors
PubMed: 34433964
DOI: 10.1038/s41586-021-03845-0 -
Nature Apr 2018Parenting is essential for the survival and wellbeing of mammalian offspring. However, we lack a circuit-level understanding of how distinct components of this behaviour...
Parenting is essential for the survival and wellbeing of mammalian offspring. However, we lack a circuit-level understanding of how distinct components of this behaviour are coordinated. Here we investigate how galanin-expressing neurons in the medial preoptic area (MPOA) of the hypothalamus coordinate motor, motivational, hormonal and social aspects of parenting in mice. These neurons integrate inputs from a large number of brain areas and the activation of these inputs depends on the animal's sex and reproductive state. Subsets of MPOA neurons form discrete pools that are defined by their projection sites. While the MPOA population is active during all episodes of parental behaviour, individual pools are tuned to characteristic aspects of parenting. Optogenetic manipulation of MPOA projections mirrors this specificity, affecting discrete parenting components. This functional organization, reminiscent of the control of motor sequences by pools of spinal cord neurons, provides a new model for how discrete elements of a social behaviour are generated at the circuit level.
Topics: Animals; Female; Galanin; Hormones; Logic; Male; Maternal Behavior; Mice; Motivation; Neural Pathways; Neurons; Optogenetics; Parenting; Paternal Behavior; Preoptic Area; Reproduction; Sex Characteristics; Social Behavior
PubMed: 29643503
DOI: 10.1038/s41586-018-0027-0 -
Nature May 2014Mice display robust, stereotyped behaviours towards pups: virgin males typically attack pups, whereas virgin females and sexually experienced males and females display...
Mice display robust, stereotyped behaviours towards pups: virgin males typically attack pups, whereas virgin females and sexually experienced males and females display parental care. Here we show that virgin males genetically impaired in vomeronasal sensing do not attack pups and are parental. Furthermore, we uncover a subset of galanin-expressing neurons in the medial preoptic area (MPOA) that are specifically activated during male and female parenting, and a different subpopulation that is activated during mating. Genetic ablation of MPOA galanin neurons results in marked impairment of parental responses in males and females and affects male mating. Optogenetic activation of these neurons in virgin males suppresses inter-male and pup-directed aggression and induces pup grooming. Thus, MPOA galanin neurons emerge as an essential regulatory node of male and female parenting behaviour and other social responses. These results provide an entry point to a circuit-level dissection of parental behaviour and its modulation by social experience.
Topics: Aggression; Animals; Copulation; Female; Galanin; Grooming; Male; Maternal Behavior; Mice; Neurons; Optogenetics; Paternal Behavior; Pheromones; Preoptic Area; TRPC Cation Channels; Vomeronasal Organ
PubMed: 24828191
DOI: 10.1038/nature13307 -
Nature Aug 2022Mating and aggression are innate social behaviours that are controlled by subcortical circuits in the extended amygdala and hypothalamus. The bed nucleus of the stria...
Mating and aggression are innate social behaviours that are controlled by subcortical circuits in the extended amygdala and hypothalamus. The bed nucleus of the stria terminalis (BNSTpr) is a node that receives input encoding sex-specific olfactory cues from the medial amygdala, and which in turn projects to hypothalamic nuclei that control mating (medial preoptic area (MPOA)) and aggression (ventromedial hypothalamus, ventrolateral subdivision (VMHvl)), respectively. Previous studies have demonstrated that male aromatase-positive BNSTpr neurons are required for mounting and attack, and may identify conspecific sex according to their overall level of activity. However, neural representations in BNSTpr, their function and their transformations in the hypothalamus have not been characterized. Here we performed calcium imaging of male BNSTpr neurons during social behaviours. We identify distinct populations of female- versus male-tuned neurons in BNSTpr, with the former outnumbering the latter by around two to one, similar to the medial amygdala and MPOA but opposite to VMHvl, in which male-tuned neurons predominate. Chemogenetic silencing of BNSTpr neurons while imaging MPOA or VMHvl neurons in behaving animals showed, unexpectedly, that the male-dominant sex-tuning bias in VMHvl was inverted to female-dominant whereas a switch from sniff- to mount-selective neurons during mating was attenuated in MPOA. Our data also indicate that BNSTpr neurons are not essential for conspecific sex identification. Rather, they control the transition from appetitive to consummatory phases of male social behaviours by shaping sex- and behaviour-specific neural representations in the hypothalamus.
Topics: Aggression; Amygdala; Animals; Calcium; Female; Hypothalamus; Male; Neurons; Preoptic Area; Sex Characteristics; Sexual Behavior, Animal; Social Behavior
PubMed: 35922505
DOI: 10.1038/s41586-022-05057-6 -
Nature Nov 2021The ability to help and care for others fosters social cohesiveness and is vital to the physical and emotional well-being of social species, including humans....
The ability to help and care for others fosters social cohesiveness and is vital to the physical and emotional well-being of social species, including humans. Affiliative social touch, such as allogrooming (grooming behaviour directed towards another individual), is a major type of prosocial behaviour that provides comfort to others. Affiliative touch serves to establish and strengthen social bonds between animals and can help to console distressed conspecifics. However, the neural circuits that promote prosocial affiliative touch have remained unclear. Here we show that mice exhibit affiliative allogrooming behaviour towards distressed partners, providing a consoling effect. The increase in allogrooming occurs in response to different types of stressors and can be elicited by olfactory cues from distressed individuals. Using microendoscopic calcium imaging, we find that neural activity in the medial amygdala (MeA) responds differentially to naive and distressed conspecifics and encodes allogrooming behaviour. Through intersectional functional manipulations, we establish a direct causal role of the MeA in controlling affiliative allogrooming and identify a select, tachykinin-expressing subpopulation of MeA GABAergic (γ-aminobutyric-acid-expressing) neurons that promote this behaviour through their projections to the medial preoptic area. Together, our study demonstrates that mice display prosocial comforting behaviour and reveals a neural circuit mechanism that underlies the encoding and control of affiliative touch during prosocial interactions.
Topics: Amygdala; Animals; Cooperative Behavior; Emotions; Female; Male; Mice; Neural Pathways; Neurons; Preoptic Area; Social Behavior; Stress, Psychological; Touch
PubMed: 34646019
DOI: 10.1038/s41586-021-03962-w