Ventromedial Nucleus Research Articles

Subunit-Specific Developmental Roles of PI3K in SF1-Expressing Cells.

Phosphatidylinositol 3-kinase (PI3K) regulates cellular development and energy homeostasis. However, the roles of its subunits in organ development remain largely unknown. We explored the roles of PI3K catalytic subunits in steroidogenic factor 1 (SF1)-expressing cells through knockout (KO) of the p110α and p110β subunits. We examined mice with a double KO of p110α and p110β in SF1-expressing cells (p110αβ KOSF1). Although these animals exhibited no significant changes in the development of the ventromedial hypothalamus, we noted pronounced hypotrophy in the adrenal cortex, testis, and ovary. Additionally, corticosterone and aldosterone levels were significantly reduced. The absence of these subunits also resulted in decreased body weight and survival rate, along with impaired glucose homeostasis, in p110αβ KOSF1 mice. The data demonstrate the specific roles of PI3K catalytic subunits in the development and function of SF1-expressing organs.

Cholecystokinin-expressing neurons of the ventromedial hypothalamic nucleus control energy homeostasis.

The hypothalamus is the primary center of the brain that regulates energy homeostasis. The ventromedial hypothalamus (VMH) plays a central role in maintaining energy balance by regulating food intake, energy expenditure, and glucose levels. However, the cellular and molecular mechanisms underlying its functions are still poorly understood. Cholecystokinin (CCK) is one of many genes expressed in this hypothalamic nucleus. Peripheral CCK regulates food intake, body weight, and glucose homeostasis. However, current research does not explain the function of CCK neurons in specific nuclei of the hypothalamus and their likely roles in network dynamics related to energy balance and food intake. This study uses genetic and pharmacological methods to examine the role of CCK-expressing neurons in the VMH (CCKVMH). Namely, using a previously generated BAC transgenic line expressing Cre recombinase under the CCK promoter, we performed targeted manipulations of CCKVMH neurons. Histological and transcriptomic database analysis revealed extensive distribution of these neurons in the VMH, with significant heterogeneity in gene expression related to energy balance, including co-expression with PACAP and somatostatin. Pharmacogenetic acute inhibition via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) resulted in increased food intake and altered meal patterns, characterized by higher meal frequency and shorter intermeal intervals. Furthermore, diphtheria toxin-mediated ablation of CCKVMH neurons led to significant weight gain and hyperphagia over time, increasing meal size and duration. These mice also exhibited impaired glucose tolerance, indicative of disrupted glucose homeostasis. Our findings underscore the integral role of CCKVMH neurons in modulating feeding behavior, energy homeostasis, and glucose regulation. This study enhances our understanding of the neurohormonal mechanisms underlying obesity and metabolic disorders, providing potential targets for therapeutic interventions.

A subcortical feeding circuit linking an interoceptive node to jaw movement.

The brain processes an array of stimuli, enabling the selection of appropriate behavioural responses, but the neural pathways linking interoceptive inputs to outputs for feeding are poorly understood1-3. Here we delineate a subcortical circuit in which brain-derived neurotrophic factor (BDNF)-expressing neurons in the ventromedial hypothalamus (VMH) directly connect interoceptive inputs to motor centres, controlling food consumption and jaw movements. VMHBDNF neuron inhibition increases food intake by gating motor sequences of feeding through projections to premotor areas of the jaw. When food is unavailable, VMHBDNF inhibition elicits consummatory behaviours directed at inanimate objects such as wooden blocks, and inhibition of perimesencephalic trigeminal area (pMe5) projections evokes rhythmic jaw movements. The activity of these neurons is decreased during food consumption and increases when food is in proximity but not consumed. Activity is also increased in obese animals and after leptin treatment. VMHBDNF neurons receive monosynaptic inputs from both agouti-related peptide (AgRP) and proopiomelanocortin neurons in the arcuate nucleus (Arc), and constitutive VMHBDNF activation blocks the orexigenic effect of AgRP activation. These data indicate an Arc → VMHBDNF → pMe5 circuit that senses the energy state of an animal and regulates consummatory behaviours in a state-dependent manner.

Functionally Separate Populations of Ventromedial Hypothalamic Neurons in Obesity and Diabetes.

The Ventromedial hypothalamic nucleus (VMN) maintains healthy metabolic function through several important roles. Collectively, homeostasis is maintained via intermingled cells within the VMN that raise blood glucose, lower blood glucose, and stimulate energy expenditure when needed. This perspective discusses the defining factors for the VMN cell types that govern distinct functions induced by the VMN, particularly in relation to energy balance and blood glucose levels. Special attention is given to distinct features of VMN cells responsible for these processes. Finally, these topics are reviewed in the context of research funded by the Pathway to Stop Diabetes initiative, highlighting key findings and current unresolved questions for future investigations.

Auditory pallial regulation of the social behavior network

Sensory cues such as vocalizations contain important social information. Processing social features of vocalizations (e.g., vocalizer identity, emotional state) necessitates unpacking the complex sound streams in song or speech; this depends on circuits in pallial cortex. But whether and how this information is then transferred to limbic and hypothalamic regions remains a mystery. Here, using gregarious, vocal songbirds (female Zebra finches), we identify a prominent influence of the auditory pallium on one specific node of the Social Behavior Network, the lateral ventromedial nucleus of the hypothalamus (VMHl). Electrophysiological recordings revealed that social and non-social auditory stimuli elicited stimulus-specific spike trains that permitted stimulus differentiation in a large majority of VMHl single units, while transient disruption of auditory pallium elevated immediate early gene activity in VMHl. Descending functional connections such as these may be critical for the range of vertebrate species that rely on nuanced communication signals to guide social decision-making.

Hypothalamic representation of the imminence of predator threat detected by the vomeronasal organ in mice.

Animals have the innate ability to select optimal defensive behaviors with appropriate intensity within specific contexts. The vomeronasal organ (VNO) serves as a primary sensory channel for detecting predator cues by relaying signals to the medial hypothalamic nuclei, particularly the ventromedial hypothalamus (VMH), which directly controls defensive behavioral outputs. Here, we demonstrate that cat saliva contains predator cues that signal the imminence of predator threat and modulate the intensity of freezing behavior through the VNO in mice. Cat saliva activates VNO neurons expressing the V2R-A4 subfamily of sensory receptors, and the number of VNO neurons activated in response to saliva correlates with both the freshness of saliva and the intensity of freezing behavior. Moreover, the number of VMH neurons activated by fresh, but not old, saliva positively correlates with the intensity of freezing behavior. Detailed analyses of the spatial distribution of activated neurons, as well as their overlap within the same individual mice, revealed that fresh and old saliva predominantly activate distinct neuronal populations within the VMH. Collectively, this study suggests that there is an accessory olfactory circuit in mice that is specifically tuned to time-sensitive components of cat saliva, which optimizes their defensive behavior to maximize their chance of survival according to the imminence of threat.

Hypothalamic representation of the imminence of predator threat detected by the vomeronasal organ in mice

Animals have the innate ability to select optimal defensive behaviors with appropriate intensity within specific contexts. The vomeronasal organ (VNO) serves as a primary sensory channel for detecting predator cues by relaying signals to the medial hypothalamic nuclei, particularly the ventromedial hypothalamus (VMH), which directly controls defensive behavioral outputs. Here, we demonstrate that cat saliva contains predator cues that signal the imminence of predator threat and modulate the intensity of freezing behavior through the VNO in mice. Cat saliva activates VNO neurons expressing the V2R-A4 subfamily of sensory receptors, and the number of VNO neurons activated in response to saliva correlates with both the freshness of saliva and the intensity of freezing behavior. Moreover, the number of VMH neurons activated by fresh, but not old, saliva positively correlates with the intensity of freezing behavior. Detailed analyses of the spatial distribution of activated neurons, as well as their overlap within the same individual mice, revealed that fresh and old saliva predominantly activate distinct neuronal populations within the VMH. Collectively, this study suggests that there is an accessory olfactory circuit in mice that is specifically tuned to time-sensitive components of cat saliva, which optimizes their defensive behavior to maximize their chance of survival according to the imminence of threat.

Cellular mechanisms of synchronized rhythmic burst generation in the ventromedial hypothalamus.

The ventromedial hypothalamus (VMH) plays an important role in feeding behavior and control of the sympathetic nervous system (SNS). The VMH includes a group of neurons that exhibit strong synchronized rhythmic burst firing (so-called VMH oscillation). This VMH oscillation is glucose inhibited, responsive to feeding-related peptides, and is functionally coupled to outputs of the SNS. However, the details of its rhythm generation and synchronization mechanisms are unknown. In the present study, we investigated cellular mechanisms of VMH oscillation by means of electrophysiological recordings and calcium imaging in juvenile rat slice preparations including the VMH. In the electrophysiological study, we performed membrane potential recording from neurons in the vicinity of pipettes for field potential recording. We found that the rhythmic bursts in the VMH were preserved in low Ca2+/high Mg2+ synaptic transmission blockade solution. During membrane hyperpolarization by current injection, the action potential was largely inhibited, but fluctuation of the membrane potential remained with a frequency similar to that at resting potential level. The electric VMH oscillation disappeared after application of either a gap junction blocker, carbenoxolone (100µM), or a persistent sodium channel blocker, riluzole (20µM). Membrane potentials and input resistances of rhythmic burst neurons in the VMH were not significantly changed during these manipulations. A calcium imaging study revealed that all VMH cells exhibiting synchronized rhythmic activity detected by intracellular calcium increases were silenced following the application of carbenoxolone. These results suggest that VMH oscillation arises from the activation of persistent sodium channels and coupling via gap junctions.

7871 Investigating The Impact Of Prenatal Exposure To A Mix Of Endocrine-Disrupting Chemicals On Development: Behavioral, Physiological, And Transcriptomic Analyses

Abstract Disclosure: M.R. Streifer: None. L. Thompson: None. A.C. Gore: None. In recent decades, there has been a growing concern surrounding the presence of endocrine-disrupting chemicals (EDCs) in our environment and their potential implications on human health. Among these, prenatal exposure and subsequent effects on the developing neuroendocrine system have emerged as a subject of interest. This study aims to define the long term developmental, behavioral, and molecular effects of prenatal exposure to NeuroMix, a complex mixture of environmentally relevant EDCs. To this end, pregnant rat dams were fed either NeuroMix or vehicle, exposing the developing fetuses during critical periods of neuroendocrine development. The exposed offspring (F1 generation) were the experimental subjects, which were allowed to mature to adulthood, underwent behavioral testing, then were euthanized for brain tissue collection. Our study revealed noteworthy sex-specific effects, whereby exposed males exhibited reduced bodyweight and anogenital index, as well as delayed puberty. In contrast, females displayed no overt developmental abnormalities but exhibited heightened risk-taking behaviors in controlled behavioral experiments like the light:dark box. To unravel the molecular underpinnings of these observed effects, 3’ Tag-sequencing and transcriptomic analyses were performed on the arcuate nucleus (ARC) and ventromedial nucleus (VMN), two hypothalamic nuclei involved in hormonal regulation, metabolism, fear-based behaviors, and development. Results of Ingenuity Pathway Analysis (IPA) unveiled differentially expressed genes in both males and females, highlighting key pathways implicated in mitochondrial dysfunction and estrogen receptor signaling. Other notable pathways identified were related to cancer, neurological disorders, and endocrine system disorders. This comprehensive investigation highlights the impact of prenatal exposure to EDCs, influencing not only physiological parameters like body weight and puberty onset, but also behavioral phenotypes indicative of neurobiological alterations. The identification of disrupted molecular pathways provides valuable insights into the potential mechanisms linking EDC exposure to adverse health outcomes, warranting further exploration and consideration in the context of human health and environmental policy. Grant support: R01 ES029464. Presentation: 6/1/2024

7753 Anoctamin 4 in the Area Postrema Regulates Glucose and Energy Homeostasis

Abstract Disclosure: L. Tu: None. Y. Xu: None. Located on the floor of the 4th ventricle within the dorsal surface of the medulla oblongata, the area postrema (AP) is a circumventricular organ where a proper blood-brain barrier is missing. Numerous studies reveal that neurons in the AP are implicated into suppression of food intake (e.g., glucagon-like peptide 1 (GLP-1)-mediated anorexia), but the role of AP neurons in whole-body glucose homeostasis is less investigated. Here we identified and fully characterized the physiological functions of anoctamin-4 (Ano4, a calcium activated chloride channel)1 in the AP. CRISPR-mediated deletion of Ano4 in the AP caused a lower body weight and reduced blood glucose, concurrent with an improved glucose tolerance and increased insulin sensitivity. Chemogenetic activation of Ano4-expressing neurons in the AP (APAno4) increased food intake and blood glucose, and did not induce conditioned flavor avoidance. Both Ano4 neurons and non-Ano4 neurons (i.e., neurons do not express Ano4) sent projections to the lateral parabrachial nucleus (LPBN). Optogenetic stimulation of APAno4 ◊ LPBN circuit promoted feeding behavior and increased blood glucose, whereas stimulation of APnon-Ano4 ◊ LPBN circuit inhibited food intake and did not influence glucose homeostasis. Finally, RNAscope studies reveal that 45.7% of APAno4 neurons are glutamatergic neurons, and 41.8% of them are GABAergic neurons. Furthermore, APAno4 neurons showed only a 2.6% overlap with Glp-1r-expressing neurons in the AP, but had a 60.8% co-localization with protein tyrosine phosphatase receptor δ2, which serves as orexigenic asprosin receptor. Together, our results indicate that Ano4 neurons in the AP are the first reported orexigenic neurons, and represent potential therapeutic targets for human diseases with glucose imbalance and abnormal feeding behavior. Reference: (1) Tu, L. et al. Anoctamin 4 channel currents activate glucose-inhibited neurons in the mouse ventromedial hypothalamus during hypoglycemia. J Clin Invest 133,14. (2023). (2) Mishra, I. et al. Protein tyrosine phosphatase receptor δ serves as the orexigenic asprosin receptor. Cell Metab 34, 549-563. (2022). Presentation: 6/2/2024

9207 Anoctamin 4 in the Area Postrema Regulates Glucose and Energy Homeostasis

Abstract Disclosure: L. Tu: None. Y. Xu: None. Located on the floor of the 4th ventricle within the dorsal surface of the medulla oblongata, the area postrema (AP) is a circumventricular organ where a proper blood-brain barrier is missing. Numerous studies reveal that neurons in the AP are implicated into suppression of food intake (e.g., glucagon-like peptide 1 (GLP-1)-mediated anorexia), but the role of AP neurons in whole-body glucose homeostasis is less investigated. Here we identified and fully characterized the physiological functions of anoctamin-4 (Ano4, a calcium activated chloride channel)1 in the AP. CRISPR-mediated deletion of Ano4 in the AP caused a lower body weight and reduced blood glucose, concurrent with an improved glucose tolerance and increased insulin sensitivity. Chemogenetic activation of Ano4-expressing neurons in the AP (APAno4) increased food intake and blood glucose, and did not induce conditioned flavor avoidance. Both Ano4 neurons and non-Ano4 neurons (i.e., neurons do not express Ano4) sent projections to the lateral parabrachial nucleus (LPBN). Optogenetic stimulation of APAno4 ◊ LPBN circuit promoted feeding behavior and increased blood glucose, whereas stimulation of APnon-Ano4 ◊ LPBN circuit inhibited food intake and did not influence glucose homeostasis. Finally, RNAscope studies reveal that 45.7% of APAno4 neurons are glutamatergic neurons, and 41.8% of them are GABAergic neurons. Furthermore, APAno4 neurons showed only a 2.6% overlap with Glp-1r-expressing neurons in the AP, but had a 60.8% co-localization with protein tyrosine phosphatase receptor δ2, which serves as orexigenic asprosin receptor. Together, our results indicate that Ano4 neurons in the AP are the first reported orexigenic neurons, and represent potential therapeutic targets for human diseases with glucose imbalance and abnormal feeding behavior. Reference: (1) Tu, L. et al. Anoctamin 4 channel currents activate glucose-inhibited neurons in the mouse ventromedial hypothalamus during hypoglycemia. J Clin Invest 133,14. (2023). (2) Mishra, I. et al. Protein tyrosine phosphatase receptor δ serves as the orexigenic asprosin receptor. Cell Metab 34, 549-563. (2022). Presentation: 6/2/2024

Hypothalamus-sympathetic-liver axis mediates the early phase of stress-induced hyperglycemia in the male mice

Rapid glucose supply is crucial for animal survival during stress response. How the timescale of stress-induced glucose release precisely controlled by hypothalamic corticotropin-releasing hormone (CRH) neurons remains unclear. Here, we show that stress-induced hyperglycemia can be divided into at least two stages in male mice: the first fast stage is mediated by hypothalamus (paraventricular to ventromedial hypothalamus)-sympathetic (raphe pallidus nucleus to intermediolateral nucleus)-liver (HSL) axis activity; the second delayed stage is mediated by adrenal activity. Blocking the activity of HSL axis impairs predatory evoked flight responses, indicating that the HSL pathway activity is necessary for stress coping. We further reveal the intracellular signal cascade for CRH signal in the hypothalamus, which is mediated by GABAA receptor β3 subunit phosphorylation at S408/409, results in prevention of GABAA receptor membrane recruitment. Thus, we uncovered the precise timescale of glucose supply during stress which is mediated by adrenal independent HSL and adrenal dependent pathway respectively.

Chronic olanzapine treatment leads to increased opioid receptor expression and changes in feeding regulating neurons in the female rat hypothalamus

Opioid receptor antagonists have shown increasing promise as an adjunct therapy to psychotropic medication. The goal is to reduce the weight gain and metabolic adverse effects that are associated with certain second-generation antipsychotics, such as olanzapine and clozapine. In this study, female rats were treated for 4 weeks with a long-acting injectable formulation of olanzapine to assess effects on hypothalamic feeding regulation. Using quantitative spatial in situ hybridization and receptor autoradiography, expression levels of the mu, kappa and delta opioid receptors were defined in the five hypothalamic areas: paraventricular nucleus (PVN), arcuate nucleus (ARC), ventromedial nucleus (VMN), dorsomedial nucleus (DMN) and lateral hypothalamus (LH). In addition, hypothalamic neuron number and size were estimated using the unbiased optical fractionator and spatial rotator methods. Hyperphagia was observed after only 24hours of olanzapine treatment, with continued weight gain throughout the duration of the study. In contrast, the observed food intake reversed to control levels after 2 weeks of olanzapine treatment. Chronic olanzapine treatment increased expression of kappa opioid receptor mRNA and receptor availability in the PVN, as well as increased mu opioid receptor availability in the PVN, ARC and VMN. These changes were accompanied by fewer anorexigenic proopiomelanocortin-expressing neurons of the ARC and corticotropin-releasing hormone expressing neurons of the PVN. This study links olanzapine-driven metabolic effects to increased opioid receptor expression in the hypothalamus, thus providing a rationale for the positive effects of using opioid receptor antagonists to relieve olanzapine adverse effects.

Effects of prenatal cocaine exposure on estrous cycle, and behavior and expression of estrogen receptor alpha and oxytocin during estrus and diestrus in mice offspring.

Increasing evidence indicates that prenatal cocaine exposure may result in many developmental and long-lasting neurological and behavioral effects. The behaviors of female animals are strongly associated with the estrous cycle. Estrogen receptors and oxytocin are important neuroendocrine factors that regulate social behavior and are of special relevance to females. However, whether prenatal cocaine exposure induces estrous cycle changes in offspring and whether neurobehavioral changes in estrus and diestrus offspring differ remains unclear. On gestational day 12, mice were administered cocaine once daily for seven consecutive days, then the estrous cycle was examined in adult female offspring, as well as locomotion, anxiety level, and social behaviors, and the expression of estrogen receptor alpha-immunoreactive and oxytocin-immunoreactive neurons were compared between estrus and diestrus offspring. Prenatal cocaine exposure resulted in the shortening of proestrus and estrus in the offspring. During estrus and diestrus, prenatally cocaine-exposed offspring showed increased anxiety levels and changed partial social behaviors; their motility showed no significant differences in estrus, but declined in diestrus. Prenatal cocaine exposure reduced estrogen receptor alpha-immunoreactive expression in the medial preoptic area, ventromedial hypothalamic nucleus, and arcuate nucleus and oxytocin-immunoreactive expression in the paraventricular nucleus in estrus and diestrus offspring. These results suggest that prenatal cocaine exposure induces changes in the offspring's estrous cycle and expression of estrogen receptor alpha and oxytocin in a brain region-specific manner and that prenatal cocaine exposure and the estrous cycle interactively change motility and partial social behavior. Estrogen receptor alpha and oxytocin signaling are likely to play important concerted roles in mediating the effects of prenatal cocaine exposure on the offspring.

The multi-stage plasticity in the aggression circuit underlying the winner effect.

Winning increases the readiness to attack and the probability of winning, a widespread phenomenon known as the "winner effect." Here, we reveal a transition from target-specific to generalized aggression enhancement over 10days of winning in male mice. This behavioral change is supported by three causally linked plasticity events in the ventrolateral part of the ventromedial hypothalamus (VMHvl), a critical node for aggression. Over 10days of winning, VMHvl cells experience monotonic potentiation of long-range excitatory inputs, transient local connectivity strengthening, and a delayed excitability increase. Optogenetically coactivating the posterior amygdala (PA) terminals and VMHvl cells potentiates the PA-VMHvl pathway and triggers the same cascade of plasticity events observed during repeated winning. Optogenetically blocking PA-VMHvl synaptic potentiation eliminates all winning-induced plasticity. These results reveal the complex Hebbian synaptic and excitability plasticity in the aggression circuit during winning, ultimately leading to increased "aggressiveness" in repeated winners.

Neuroethology: A Review of Studies on Combat Behavior in Mice

Optogenetics has revolutionized neuroscience, enabling precise control and monitoring of neural circuits. This study focuses on the neural mechanisms underlying combat behaviors in mice, particularly the roles of the ventromedial hypothalamus (VMH) in freezing, jumping escape, and defensive attack behaviors. The research employed a combination of optogenetic tools, behavioral assays, and high-resolution imaging techniques. Genetically modified mice expressing channelrhodopsin-2 (ChR2) and halorhodopsin (NpHR) were used. Viral vectors were injected into specific brain regions, and optogenetic stimulation was performed to activate or inhibit neuronal populations. Behavioral responses were documented and analyzed using specialized software, and brain tissues were prepared for histological examination. Activation of VMH neurons increased jumping escape behavior, while inhibition reduced defensive attack behaviors, highlighting the VMH's critical role in these responses. High-resolution video analysis provided detailed metrics on behavior, and histological examination confirmed precise targeting and expression of optogenetic proteins in the brain. The results demonstrated the direct influence of specific neural circuits on combat behaviors. The study elucidated the roles of VMH and associated neural circuits in mediating combat behaviors in mice. Optogenetic techniques provided precise control over neuronal activity, revealing critical insights into the neural mechanisms underlying these behaviors. The findings support the VMH's central role in regulating instinctual defensive actions and offer potential applications for developing therapeutic strategies for anxiety and pain disorders.

Estrous cycle-dependent modulation of sexual receptivity in female mice by estrogen receptor beta-expressing cells in the dorsal raphe nucleus

The sexual receptivity of female mice, shown as lordosis response, is mainly regulated by estradiol action on estrogen receptor alpha (ERα) and beta (ERβ), depending on the day of the estrous cycle. Previous studies revealed that ERα in the ventromedial nucleus of the hypothalamus (VMH) plays an essential role in the induction of lordosis on the day of estrus (Day 1). However, the mechanisms of the transition to non-receptive states on the day after estrus (Day 2) are not completely understood. In the present study, we investigated the possible role of ERβ, which is highly expressed in the dorsal raphe nucleus (DRN), in lordosis expression. We found that ERβ-Cre female mice, which were ovariectomized and primed with estradiol and progesterone to mimic the estrous cycle, showed high levels of lordosis on Day 2 when ERβ-expressing DRN (DRN-ERβ+) neuronal activity was chemogenetically suppressed. This finding suggests that excitation of DRN-ERβ+ neurons is necessary for the decline of lordosis on Day 2. Fiber photometry recordings during female-male behavioral interactions revealed that DRN-ERβ+ neuronal activation in response to male intromission was significantly more prolonged on Day 2 compared to Day 1. Chemogenetic over-stimulation of DRN-ERβ+ neurons induced c-Fos expression in brain areas known to be inhibitory for lordosis expression, even though they did not express anterogradely labeled fibers of DRN-ERβ+ cells. These findings collectively suggest that DRN-ERβ+ neuronal excitation serves as an inhibitory modulator and is responsible for the decline in receptivity during non-estrus phases.Significance StatementIn females, switching from a sexually receptive state to a non-receptive phase during the estrous cycle is essential for effective behavioral interactions with males and successful reproduction. Here, we delineate the possible brain regions that regulate the decline in receptive behavioral responses, such as lordosis, from those shown on the day of estrus to those on the day after estrus. We found that excitation of neurons expressing estrogen receptor (ER) β in the midbrain dorsal raphe nucleus is crucial for the suppression of lordosis during the day after estrus. This is contrasted with the facilitatory action of ERα, another type of ER, and provides new insights for understanding the neural basis of the adaptive expression of female reproductive behavior.

Thyroid Hormone Clearance in the Paraventricular Nucleus of Male Mice Regulates Lean Mass and Physical Activity

Introduction: The actions of thyroid hormones (THs) in the central nervous system are relevant to food intake and energy expenditure. TH receptors exhibit high expression in brain areas modulating energy balance, including the arcuate, paraventricular (PVN), supraoptic, and ventromedial (VMH) hypothalamic nuclei. Methods: To examine the role of THs in the regulation of energy balance via action in specific hypothalamic nuclei of the adult mouse, we performed experiments of conditional inactivation of DIO3, the enzyme responsible for the clearance of THs, in the lateral hypothalamus (LH), and VMH and PVN hypothalamic nuclei. We accomplished DIO3 genetic inactivation via stereotaxic injection of the AAV-cre vector into adult mice homozygous for a “floxed” Dio3 allele. Results: Dio3 inactivation in the LH and VMH of males or females did not result in significant changes in body weight 8 weeks after injection. However, inactivation of Dio3 in the PVN resulted in increased body weight (both fat mass and lean mass) and locomotor activity, and decreased hypothalamic Mc4r expression in male, but not female mice. However, PNV-specific Dio3 KO did not cause hyperphagia. Conclusion: These results suggest local TH action influences MC4R signaling and possibly other PVN-associated circuitries, with consequences for body composition and energy balance endpoints, but not for orexigenic pathways. They also support a regulatory role for PVN Dio3 in the central regulation of energy homeostasis in adult life.

Distinct medial amygdala oxytocin receptor neurons projections respectively control consolation or aggression in male mandarin voles

The individuals often show consolation to distressed companions or show aggression to the intruders. The circuit mechanisms underlying switching between consolation and aggression remain unclear. In the present study, using male mandarin voles, we identified that two distinct subtypes of oxytocin receptor (OXTR) neurons in the medial amygdala (MeA) projecting to the anterior insula (AI) and ventrolateral aspect of ventromedial hypothalamus (VMHvl) response differently to stressed siblings or unfamiliar intruders using c-Fos or calcium recording. Oxytocin release and activities of PVN neurons projecting to MeA increased upon consoling and attacking. OXTR antagonist injection to the MeA reduced consoling and attacking. Apoptosis, optogenetic or pharmacogenetic manipulation of these two populations of neurons altered behavioral responses to these two social stimuli respectively. Here, we show that two subtypes of OXTR neurons in the MeA projecting to the AI or VMHvl causally control consolation or aggression that may underlie switch between consolation and aggression.

Functional diversity along the anteroposterior axis of the ventromedial hypothalamus.

Innate behaviors ensure animal survival and reproductive success. Defending their territory, escaping from predators or mating with a sexual partner, are fundamental behaviors determining the ecological fitness of individuals. Remarkably, all these behaviors share a common neural substrate, as they are under the control of the ventromedial hypothalamus (VMH). Decades of research have contributed to understanding the exquisite diversity of functional ensembles underlying the wide array of functions that the VMH carries out. These functional ensembles are usually distributed throughout the dorsoventral and mediolateral axes of this nucleus. However, increasing evidence is bringing to attention the functional diversity of the VMH across its anteroposterior axis. In this review, we will overview our current understanding of how different ensembles within the VMH control a wide array of animal behaviors, emphasizing the newly discovered roles for its anterior subdivision in the context of conspecific self-defense.