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Mammalian reproductive function depends upon a neuroendocrine circuit that evokes the pulsatile release of gonadotropin hormones (luteinizing hormone and follicle-stimulating hormone) from the pituitary. This reproductive circuit is sensitive to metabolic perturbations. When challenged with starvation, insufficient energy reserves attenuate gonadotropin release, leading to infertility. The reproductive neuroendocrine circuit is well established, composed of two populations of kisspeptin-expressing neurons (located in the anteroventral periventricular hypothalamus, Kiss1AVPV, and arcuate hypothalamus, Kiss1ARH), which drive the pulsatile activity of gonadotropin-releasing hormone (GnRH) neurons. The reproductive axis is primarily regulated by gonadal steroid and circadian cues, but the starvation-sensitive input that inhibits this circuit during negative energy balance remains controversial. Agouti-related peptide (AgRP)-expressing neurons are activated during starvation and have been implicated in leptin-associated infertility. To test whether these neurons relay information to the reproductive circuit, we used AgRP-neuron ablation and optogenetics to explore connectivity in acute slice preparations. Stimulation of AgRP fibers revealed direct, inhibitory synaptic connections with Kiss1ARH and Kiss1AVPV neurons. In agreement with this finding, Kiss1ARH neurons received less presynaptic inhibition in the absence of AgRP neurons (neonatal toxin-induced ablation). To determine whether enhancing the activity of AgRP neurons is sufficient to attenuate fertility in vivo, we artificially activated them over a sustained period and monitored fertility. Chemogenetic activation with clozapine N-oxide resulted in delayed estrous cycles and decreased fertility. These findings are consistent with the idea that, during metabolic deficiency, AgRP signaling contributes to infertility by inhibiting Kiss1 neurons.

Proper body weight is determined by orexigenic and anorexigenic neurons in the hypothalamus. Lori Zeltser and her colleagues have found that a subset of neurons in the developing hypothalamus expressing a potent orexigenic hormone is derived from precursors expressing an anorexigenic hormone. These results suggest that developing feeding circuits are more plastic than previously thought and give rise to new concerns about the effects of a mother's diet during pregnancy on her offspring. Hypothalamic neuron circuits regulating energy balance are highly plastic and develop in response to nutrient and hormonal cues. To identify processes that might be susceptible to gestational influences in mice, we characterized the ontogeny of proopiomelanocortin (POMC) and neuropeptide Y (NPY) cell populations, which exert opposing influences on food intake and body weight. These analyses revealed that Pomc is broadly expressed in immature hypothalamic neurons and that half of embryonic Pomc -expressing precursors subsequently adopt a non-POMC fate in adult mice. Moreover, nearly one quarter of the mature NPY + cell population shares a common progenitor with POMC + cells.

Kisspeptin (Kiss1) and neurokinin B (NKB) neurocircuits are essential for pubertal development and fertility. Kisspeptin neurons in the hypothalamic arcuate nucleus (Kiss1ARH) co-express Kiss1, NKB, dynorphin and glutamate and are postulated to provide an episodic, excitatory drive to gonadotropin-releasing hormone 1 (GnRH) neurons, the synaptic mechanisms of which are unknown. We characterized the cellular basis for synchronized Kiss1ARH neuronal activity using optogenetics, whole-cell electrophysiology, molecular pharmacology and single cell RT-PCR in mice. High-frequency photostimulation of Kiss1ARH neurons evoked local release of excitatory (NKB) and inhibitory (dynorphin) neuropeptides, which were found to synchronize the Kiss1ARH neuronal firing. The light-evoked synchronous activity caused robust excitation of GnRH neurons by a synaptic mechanism that also involved glutamatergic input to preoptic Kiss1 neurons from Kiss1ARH neurons. We propose that Kiss1ARH neurons play a dual role of driving episodic secretion of GnRH through the differential release of peptide and amino acid neurotransmitters to coordinate reproductive function. Puberty and fertility are necessary for survival of the species. An evolutionarily ancient region of the brain called the hypothalamus regulates these processes. The hypothalamus releases a chemical messenger called gonadotropin-releasing hormone (or GnRH for short), which is then transported from the brain to the pituitary gland. GnRH activates the pituitary gland, which in turn releases reproductive hormones that control ovulation in females and sperm production in males. For this process to work correctly in females, the hypothalamus must release GnRH in appropriately timed pulses and produce one massive release, or “surge”, of GnRH to trigger ovulation. Two populations of neurons within the hypothalamus produce a peptide molecule called Kisspeptin and drive the activity and subsequent release of GnRH. One population resides in an area called the arcuate nucleus and the other in the preoptic nucleus. Recent findings suggest that the arcuate nucleus is the “pulse generator” responsible for triggering the rhythmic release of GnRH by the hypothalamus, whereas the preoptic nucleus induces the surge of GnRH. However, how these brain regions do this remains unclear. Using a technique called optogenetics, Qiu, Nestor et al. explored whether kisspeptin-producing neurons in the arcuate nucleus are able to communicate with each other to drive pulses of GnRH release. The idea was to selectively activate a subset of kisspeptin neurons in mice and determine whether this would activate the remaining neurons at the same time. Qiu, Nestor et al. introduced a light-sensitive protein into the kisspeptin-producing neurons on one side of the arcuate nucleus, and then used light to activate those neurons. As predicted, this caused kisspeptin neurons throughout the arcuate nucleus to coordinate their activity. In addition to their namesake peptide, kisspeptin-producing neurons also make the neurotransmitter glutamate, the excitatory peptide neurokinin B, and the inhibitory peptide dynorphin. Light-induced stimulation of the arcuate nucleus caused its kisspeptin neurons to also release neurokinin B and dynorphin, which synchronized the firing of the kisspeptin neurons. The hypothalamus then translates this coordinated activity into pulses of GnRH release. The light-induced stimulation also triggered the release of glutamate, which caused kisspeptin neurons within the preoptic nucleus to fire in bursts. This in turn robustly excited the GnRH neurons, giving rise to the surge of GnRH. These findings show that peptide and classical neurotransmitters collaborate to control GnRH neuron activity and, consequently, fertility. The results obtained by Qiu, Nestor et al. can be used to further explore kisspeptin-GnRH neuronal circuits, and to obtain insights into the role of neuronal peptide signaling in healthy as well as diseased states.

The neuropeptides tachykinin2 (Tac2) and kisspeptin (Kiss1) in hypothalamic arcuate nucleus Kiss1 (Kiss1ARH) neurons are essential for pulsatile release of GnRH and reproduction. Since 17β-estradiol (E2) decreases Kiss1 and Tac2 mRNA expression in Kiss1ARH neurons, the role of Kiss1ARH neurons during E2-driven anorexigenic states and their coordination of POMC and NPY/AgRP feeding circuits have been largely ignored. Presently, we show that E2 augmented the excitability of Kiss1ARH neurons by amplifying Cacna1g, Hcn1 and Hcn2 mRNA expression and T-type calcium and h-currents. E2 increased Slc17a6 mRNA expression and glutamatergic synaptic input to arcuate neurons, which excited POMC and inhibited NPY/AgRP neurons via metabotropic receptors. Deleting Slc17a6 in Kiss1 neurons eliminated glutamate release and led to conditioned place preference for sucrose in E2-treated KO female mice. Therefore, the E2-driven increase in Kiss1 neuronal excitability and glutamate neurotransmission may play a key role in governing the motivational drive for palatable food in females.

Complex social behaviors are emergent properties of the brain’s many interconnected and overlapping neural networks. Questions aimed at understanding how brain circuits produce specific and appropriate behaviors have changed over the past half century, shifting from studies of gross anatomical and behavioral associations, to manipulating and monitoring precisely targeted cell types. This technical progression has enabled increasingly deep insights into the regulation of perception and behavior with remarkable precision. The capacity of these reductionist approaches to identify the function of isolated circuits is undeniable but many behaviors require rapid integration of diverse inputs. It is now possible to simultaneously observe circuit activity at multiple nodes of a network. This review examines progress in our understanding of social circuits as an example of how our understanding of brain circuits and their functions developed in conjunction with technologies for visualizing and manipulating neurons and considers how new techniques may allow us to address brain circuit function in the context of integrative and recursive anatomy.

In mice, the ovarian hormone oestradiol sensitizes neurons in a brain region called the hypothalamus to a melanocortin hormone that signals an energy surplus. Their dual activation increases physical activity. An oestrogen sensitizes certain neurons to signals of energy surplus.

Neurokinin B (NKB) signaling is critical for reproduction in all studied species. The existing consensus is that NKB induces GnRH release via kisspeptin (Kiss1) stimulation in the arcuate nucleus. However, the stimulatory action of NKB is dependent on circulating estrogen (E2) levels, without which, NKB inhibits luteinizing hormone (LH) release. Importantly, the evidence supporting the kisspeptin-dependent role of NKB, derives from models of persistent hypogonadal state [e.g. Kiss1r knock-out (KO) mice], with reduced E2 levels. Here, we demonstrate that in the presence of E2, NKB signaling induces LH release in a kisspeptin-independent manner through the activation of NK3R (NKB receptor) neurons in the posterodorsal medial amygdala (MePD). Importantly, we show that chemogenetic activation of MePD Kiss1 neurons induces LH release, however, the stimulatory action of NKB in this area is Kiss1 neuron-independent. These results document the existence of two independent neuronal circuitries within the MePD that regulate reproductive function in females. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter ).

Starving animals are less likely to defend their home territory and more likely to engage in risky foraging behaviors. This work describes a circuit involving hypothalamic AgRP neurons projecting to neurons in the medial nucleus of the amygdala and their projections to the bed nucleus of the stria terminalis, which, when activated, mimics these behaviors in mice that are well fed. In the face of starvation, animals will engage in high-risk behaviors that would normally be considered maladaptive. Starving rodents, for example, will forage in areas that are more susceptible to predators and will also modulate aggressive behavior within a territory of limited or depleted nutrients. The neural basis of these adaptive behaviors likely involves circuits that link innate feeding, aggression and fear. Hypothalamic agouti-related peptide (AgRP)-expressing neurons are critically important for driving feeding and project axons to brain regions implicated in aggression and fear. Using circuit-mapping techniques in mice, we define a disynaptic network originating from a subset of AgRP neurons that project to the medial nucleus of the amygdala and then to the principal bed nucleus of the stria terminalis, which suppresses territorial aggression and reduces contextual fear. We propose that AgRP neurons serve as a master switch capable of coordinating behavioral decisions relative to internal state and environmental cues.

Maintaining energy homeostasis requires coordinating physiology and behavior both on an acute timescale to adapt to rapid fluctuations in caloric intake and on a chronic timescale to regulate body composition. Hypothalamic agouti-related peptide (AgRP)-expressing neurons are acutely activated by caloric need, and this acute activation promotes increased food intake and decreased energy expenditure. On a longer timescale, AgRP neurons exhibit chronic hyperactivity under conditions of obesity and high dietary fat consumption, likely due to leptin resistance; however, the behavioral and metabolic effects of chronic AgRP neuronal hyperactivity remain unexplored. Here, we use chemogenetics to manipulate Gq signaling in AgRP neurons in mice to explore the hypothesis that chronic activation of AgRP neurons promotes obesity. Inducing chronic Gq signaling in AgRP neurons initially increased food intake and caused dramatic weight gain, in agreement with published data; however, food intake returned to baseline levels within 1 wk, and body weight returned to baseline levels within 60 d. Additionally, we found that, when mice had elevated body weight due to chronic Gq signaling in AgRP neurons, energy expenditure was not altered but adiposity and lipid metabolism were both increased, even under caloric restriction. These findings reveal that the metabolic and behavioral effects of chronic Gq signaling in AgRP neurons are distinct from the previously reported effects of acute Gq signaling and also of leptin insensitivity.

Mammals maintain energy homeostasis and a stable body weight via neural circuits that regulate food intake and metabolism. Understanding how signaling within these circuits influences feeding, metabolism, and body weight is critical for understanding and treating diseases involving altered energy homeostasis, such as obesity and cachexia. Hypothalamic AgRP-expressing neurons are known to induce hyperphagia and decrease energy expenditure when acutely activated; however, the effects of chronic hyperactivity in AgRP neurons—which occurs in obese individuals—are unknown. Here, we show that chronic G q -mediated activation of AgRP neurons in mice does not cause long-lasting obesogenic changes in feeding, body weight, gut microbiome, or energy expenditure, but does cause increased adiposity and increased lipid metabolism, even under caloric restriction. Maintaining energy homeostasis requires coordinating physiology and behavior both on an acute timescale to adapt to rapid fluctuations in caloric intake and on a chronic timescale to regulate body composition. Hypothalamic agouti-related peptide (AgRP)-expressing neurons are acutely activated by caloric need, and this acute activation promotes increased food intake and decreased energy expenditure. On a longer timescale, AgRP neurons exhibit chronic hyperactivity under conditions of obesity and high dietary fat consumption, likely due to leptin resistance; however, the behavioral and metabolic effects of chronic AgRP neuronal hyperactivity remain unexplored. Here, we use chemogenetics to manipulate G q signaling in AgRP neurons in mice to explore the hypothesis that chronic activation of AgRP neurons promotes obesity. Inducing chronic G q signaling in AgRP neurons initially increased food intake and caused dramatic weight gain, in agreement with published data; however, food intake returned to baseline levels within 1 wk, and body weight returned to baseline levels within 60 d. Additionally, we found that, when mice had elevated body weight due to chronic G q signaling in AgRP neurons, energy expenditure was not altered but adiposity and lipid metabolism were both increased, even under caloric restriction. These findings reveal that the metabolic and behavioral effects of chronic G q signaling in AgRP neurons are distinct from the previously reported effects of acute G q signaling and also of leptin insensitivity.