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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 Neuroscience Sep 2023Fluctuations in reproductive hormone levels are associated with mood disruptions in women, such as in postpartum and perimenopausal depression. However, the neural...
Fluctuations in reproductive hormone levels are associated with mood disruptions in women, such as in postpartum and perimenopausal depression. However, the neural circuit mechanisms remain unclear. Here we report that medial preoptic area (MPOA) GABAergic neurons mediate multifaceted depressive-like behaviors in female mice after ovarian hormone withdrawal (HW), which can be attributed to downregulation of activity in Esr1 (estrogen receptor-1)-expressing GABAergic neurons. Enhancing activity of these neurons ameliorates depressive-like behaviors in HW-treated mice, whereas reducing their activity results in expression of these behaviors. Two separate subpopulations mediate different symptoms: a subpopulation projecting to the ventral tegmental area (VTA) mediates anhedonia and another projecting to the periaqueductal gray mediates immobility. These projections enhance activity of dopaminergic neurons in the VTA and serotonergic neurons in the dorsal raphe, respectively, with increased release of dopamine and serotonin, possibly through disinhibition mechanisms. Thus, the MPOA is a hub that mediates depressive-like behaviors resulting from transitions in reproductive hormone levels.
Topics: Mice; Female; Animals; Preoptic Area; Ventral Tegmental Area; Dopaminergic Neurons; GABAergic Neurons
PubMed: 37524978
DOI: 10.1038/s41593-023-01397-2 -
Nature Jan 2021Animal behaviours that are superficially similar can express different intents in different contexts, but how this flexibility is achieved at the level of neural...
Animal behaviours that are superficially similar can express different intents in different contexts, but how this flexibility is achieved at the level of neural circuits is not understood. For example, males of many species can exhibit mounting behaviour towards same- or opposite-sex conspecifics, but it is unclear whether the intent and neural encoding of these behaviours are similar or different. Here we show that female- and male-directed mounting in male laboratory mice are distinguishable by the presence or absence of ultrasonic vocalizations (USVs), respectively. These and additional behavioural data suggest that most male-directed mounting is aggressive, although in rare cases it can be sexual. We investigated whether USV and USV mounting use the same or distinct hypothalamic neural substrates. Micro-endoscopic imaging of neurons positive for oestrogen receptor 1 (ESR1) in either the medial preoptic area (MPOA) or the ventromedial hypothalamus, ventrolateral subdivision (VMHvl) revealed distinct patterns of neuronal activity during USV and USV mounting, and the type of mounting could be decoded from population activity in either region. Intersectional optogenetic stimulation of MPOA neurons that express ESR1 and vesicular GABA transporter (VGAT) (MPOA neurons) robustly promoted USV mounting, and converted male-directed attack to mounting with USVs. By contrast, stimulation of VMHvl neurons that express ESR1 (VMHvl neurons) promoted USV mounting, and inhibited the USVs evoked by female urine. Terminal stimulation experiments suggest that these complementary inhibitory effects are mediated by reciprocal projections between the MPOA and VMHvl. Together, these data identify a hypothalamic subpopulation that is genetically enriched for neurons that causally induce a male reproductive behavioural state, and indicate that reproductive and aggressive states are represented by distinct population codes distributed between MPOA and VMHvl neurons, respectively. Thus, similar behaviours that express different internal states are encoded by distinct hypothalamic neuronal populations.
Topics: Aggression; Animals; Copulation; Estrogen Receptor alpha; Female; Homosexuality, Male; Hypothalamus; Male; Mice; Optogenetics; Preoptic Area; Sexual Behavior, Animal; Vesicular Inhibitory Amino Acid Transport Proteins
PubMed: 33268894
DOI: 10.1038/s41586-020-2995-0 -
Neuron Feb 2023Precise monitoring of internal temperature is vital for thermal homeostasis in mammals. For decades, warm-sensitive neurons (WSNs) within the preoptic area (POA) were...
Precise monitoring of internal temperature is vital for thermal homeostasis in mammals. For decades, warm-sensitive neurons (WSNs) within the preoptic area (POA) were thought to sense internal warmth, using this information as feedback to regulate body temperature (T). However, the cellular and molecular mechanisms by which WSNs measure temperature remain largely undefined. Via a pilot genetic screen, we found that silencing the TRPC4 channel in mice substantially attenuated hypothermia induced by light-mediated heating of the POA. Loss-of-function studies of TRPC4 confirmed its role in warm sensing in GABAergic WSNs, causing additional defects in basal temperature setting, warm defense, and fever responses. Furthermore, TRPC4 antagonists and agonists bidirectionally regulated T. Thus, our data indicate that TRPC4 is essential for sensing internal warmth and that TRPC4-expressing GABAergic WSNs function as a novel cellular sensor for preventing T from exceeding set-point temperatures. TRPC4 may represent a potential therapeutic target for managing T.
Topics: Mice; Animals; Body Temperature; Body Temperature Regulation; Hypothalamus; Preoptic Area; GABAergic Neurons; Mammals
PubMed: 36476978
DOI: 10.1016/j.neuron.2022.11.008 -
Current Biology : CB Dec 2023Endotherms can survive low temperatures and food shortage by actively entering a hypometabolic state known as torpor. Although the decrease in metabolic rate and body...
Endotherms can survive low temperatures and food shortage by actively entering a hypometabolic state known as torpor. Although the decrease in metabolic rate and body temperature (Tb) during torpor is controlled by the brain, the specific neural circuits underlying these processes have not been comprehensively elucidated. In this study, we identify the neural circuits involved in torpor regulation by combining whole-brain mapping of torpor-activated neurons, cell-type-specific manipulation of neural activity, and viral tracing-based circuit mapping. We find that Trpm2-positive neurons in the preoptic area and Vgat-positive neurons in the dorsal medial hypothalamus are activated during torpor. Genetic silencing shows that the activity of either cell type is necessary to enter the torpor state. Finally, we show that these cells receive projections from the arcuate and suprachiasmatic nucleus and send projections to brain regions involved in thermoregulation. Our results demonstrate an essential role of hypothalamic neurons in the regulation of Tb and metabolic rate during torpor and identify critical nodes of the torpor regulatory network.
Topics: Hypothalamus; Torpor; Preoptic Area; Suprachiasmatic Nucleus; Brain
PubMed: 37992720
DOI: 10.1016/j.cub.2023.10.076 -
CNS Neuroscience & Therapeutics Dec 2023The lateral periaqueductal gray (LPAG), which mainly contains glutamatergic neurons, plays an important role in social responses, pain, and offensive and defensive...
OBJECTIVE
The lateral periaqueductal gray (LPAG), which mainly contains glutamatergic neurons, plays an important role in social responses, pain, and offensive and defensive behaviors. Currently, the whole-brain monosynaptic inputs to LPAG glutamatergic neurons are unknown. This study aims to explore the structural framework of the underlying neural mechanisms of LPAG glutamatergic neurons.
METHODS
This study used retrograde tracing systems based on the rabies virus, Cre-LoxP technology, and immunofluorescence analysis.
RESULTS
We found that 59 nuclei projected monosynaptic inputs to the LPAG glutamatergic neurons. In addition, seven hypothalamic nuclei, namely the lateral hypothalamic area (LH), lateral preoptic area (LPO), substantia innominata (SI), medial preoptic area, ventral pallidum, posterior hypothalamic area, and lateral globus pallidus, projected most densely to the LPAG glutamatergic neurons. Notably, we discovered through further immunofluorescence analysis that the inputs to the LPAG glutamatergic neurons were colocalized with several markers related to important neurological functions associated with physiological behaviors.
CONCLUSION
The LPAG glutamatergic neurons received dense projections from the hypothalamus, especially nuclei such as LH, LPO, and SI. The input neurons were colocalized with several markers of physiological behaviors, which show the pivotal role of glutamatergic neurons in the physiological behaviors regulation by LPAG.
Topics: Mice; Animals; Periaqueductal Gray; Brain; Neurons; Hypothalamus; Preoptic Area
PubMed: 37424163
DOI: 10.1111/cns.14338 -
Neuroendocrinology 2018The preoptic area (POA) of the hypothalamus is involved in many physiological and behavioral processes thanks to its interconnections to many brain areas and ability to... (Review)
Review
The preoptic area (POA) of the hypothalamus is involved in many physiological and behavioral processes thanks to its interconnections to many brain areas and ability to respond to diverse humoral factors. One main function of the POA is to manage body temperature homeostasis, e.g. in response to ambient temperature change, which is achieved in part by controlling brown adipose tissue thermogenesis. The POA is also importantly involved in modulating food intake in response to temperature change, thus making it relevant for body weight homeostasis and obesity research. POA function in body weight control is highly unexplored, and a better understanding of POA circuits and their integration into classic hypothalamic circuits that regulate energy homeostasis is expected to provide new opportunities for the scientific basis and treatment of obesity and comorbidities.
Topics: Animals; Body Weight; Homeostasis; Humans; Preoptic Area; Temperature
PubMed: 28772276
DOI: 10.1159/000479875 -
Lateral preoptic area glutamate neurons relay nociceptive information to the ventral tegmental area.Cell Reports Sep 2023The ventral tegmental area (VTA) has been proposed to play a role in pain, but the brain structures modulating VTA activity in response to nociceptive stimuli remain...
The ventral tegmental area (VTA) has been proposed to play a role in pain, but the brain structures modulating VTA activity in response to nociceptive stimuli remain unclear. Here, we demonstrate that the lateral preoptic area (LPO) glutamate neurons relay nociceptive information to the VTA. These LPO glutamatergic neurons synapsing on VTA neurons respond to nociceptive stimulation and conditioned stimuli predicting nociceptive stimulation and also mediate aversion. In contrast, LPO GABA neurons synapsing in the VTA mediate reward. By ultrastructural quantitative synaptic analysis, ex vivo electrophysiology, and functional neuroanatomy we identify a complex circuitry between LPO glutamatergic and GABAergic neurons and VTA dopaminergic, GABAergic, and glutamatergic neurons. We conclude that LPO glutamatergic neurons play a causal role in the processing of nociceptive stimuli and in relaying information about nociceptive stimuli. The pathway from LPO glutamatergic neurons to the VTA represents an unpredicted interface between peripheral nociceptive information and the limbic system.
Topics: Glutamic Acid; Ventral Tegmental Area; Preoptic Area; Nociception; GABAergic Neurons; Dopaminergic Neurons
PubMed: 37632750
DOI: 10.1016/j.celrep.2023.113029 -
Handbook of Clinical Neurology 2021The preoptic area of the hypothalamus is the central hub of thermoregulation in mammals, coordinating autonomic heat-effector pathways in response to sensory information... (Review)
Review
The preoptic area of the hypothalamus is the central hub of thermoregulation in mammals, coordinating autonomic heat-effector pathways in response to sensory information from the ambient and internal environment. This aims to maintain temperature homeostasis at a predetermined thermoregulatory set-point. However, hormonal and neuronal changes during the menopause, including estrogen deficiency, disrupt these normal thermoregulatory responses. This results in abnormal activation of heat dissipation effectors, manifesting clinically as hot flush symptoms. Neurokinin B (NKB) signaling via the neurokinin-3 receptor (NK3R) within the preoptic area is thought to play an important role in the pathophysiology of hot flushes. Therefore attenuation of the NKB/NK3R signaling pathway has garnered much interest as a novel therapeutic target for the amelioration of menopausal hot flushes. Recent clinical trials have demonstrated that NK3R antagonists can produce rapid and sustained improvements in hot flush frequency, severity, and quality of life, without the need for estrogen exposure. Therefore NK3R antagonists are fast emerging as a safe and efficacious alternative to hormone replacement therapy, the current gold standard of treatment.
Topics: Animals; Female; Hot Flashes; Humans; Menopause; Neuroendocrinology; Preoptic Area; Quality of Life
PubMed: 34225982
DOI: 10.1016/B978-0-12-819975-6.00029-7 -
The Journal of Neuroscience : the... May 2023To understand how sleep-wakefulness cycles are regulated, it is essential to disentangle structural and functional relationships between the preoptic area (POA) and...
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 and VLPO 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 hybridization (ISH) in male and female mice, we revealed that the vesicular GABA transporter ()- and galanin ()-expressing neurons in the VLPO directly synapse with orexin neurons in the LHA. A majority (56.3 ± 8.1%) of all VLPO input neurons connecting to orexin neurons were double-positive for and Using projection-specific rabies virus-mediated tracing in male and female and mice, we discovered that VLPO and VLPO 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 neurons, but not VLPO neurons, in the LHA of male 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→LHA pathway in the regulation of sleep and wakefulness. We identified neurons in the ventrolateral preoptic nucleus (VLPO) that are positive for vesicular GABA transporter () and/or galanin () and serve as presynaptic partners of orexin-producing neurons in the lateral hypothalamic area (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 the VLPO→LHA pathway, but not the VLPO→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→LHA pathway in sleep-wakefulness regulation. Furthermore, we suggest the existence of subpopulations of VLPO neurons that innervate LHA.
Topics: Mice; Male; Female; Animals; Preoptic Area; Hypothalamic Area, Lateral; Orexins; Galanin; Neurons; Wakefulness; Sleep; gamma-Aminobutyric Acid
PubMed: 37117013
DOI: 10.1523/JNEUROSCI.1913-22.2023