Hunger is controlled by specialized neural circuits that translate homeostatic needs into motivated behaviors. These circuits are under chronic control by circulating signals of nutritional state, ...but their rapid dynamics on the timescale of behavior remain unknown. Here, we report optical recording of the natural activity of two key cell types that control food intake, AgRP and POMC neurons, in awake behaving mice. We find unexpectedly that the sensory detection of food is sufficient to rapidly reverse the activation state of these neurons induced by energy deficit. This rapid regulation is cell-type specific, modulated by food palatability and nutritional state, and occurs before any food is consumed. These data reveal that AgRP and POMC neurons receive real-time information about the availability of food in the external world, suggesting a primary role for these neurons in controlling appetitive behaviors such as foraging that promote the discovery of food.
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•Sensory detection of food rapidly inhibits AgRP and activates POMC neurons•Rapid sensory feedback occurs before any food is consumed•The magnitude of neuronal response depends on food palatability and nutritional state•AgRP/POMC neurons may play a primary role in driving food discovery
Simply presenting food to a hungry mouse resets the activity of its AgRP and POMC neurons from a pattern associated with energy deficit to one associated with satiety, even if no food is consumed. The extent of the neuronal activity changes depends on the accessibility and palatability of the food.
The regulation of body temperature is one of the most critical functions of the nervous system. Here we review our current understanding of thermoregulation in mammals. We outline the molecules and ...cells that measure body temperature in the periphery, the neural pathways that communicate this information to the brain, and the central circuits that coordinate the homeostatic response. We also discuss some of the key unresolved issues in this field, including the following: the role of temperature sensing in the brain, the molecular identity of the warm sensor, the central representation of the labeled line for cold, and the neural substrates of thermoregulatory behavior. We suggest that approaches for molecularly defined circuit analysis will provide new insight into these topics in the near future.
Tan and Knight review the neural mechanisms that regulate body temperature in mammals. They describe the molecules and cells that sense temperature, the afferent pathways that transmit this information to the brain, and efferent pathways that coordinate the homeostatic response.
The mammalian brain is composed of thousands of interacting neural cell types. Systematic approaches to establish the molecular identity of functional populations of neurons would advance our ...understanding of neural mechanisms controlling behavior. Here, we show that ribosomal protein S6, a structural component of the ribosome, becomes phosphorylated in neurons activated by a wide range of stimuli. We show that these phosphorylated ribosomes can be captured from mouse brain homogenates, thereby enriching directly for the mRNAs expressed in discrete subpopulations of activated cells. We use this approach to identify neurons in the hypothalamus regulated by changes in salt balance or food availability. We show that galanin neurons are activated by fasting and that prodynorphin neurons restrain food intake during scheduled feeding. These studies identify elements of the neural circuit that controls food intake and illustrate how the activity-dependent capture of cell-type-specific transcripts can elucidate the functional organization of a complex tissue.
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► Ribosomal protein S6 becomes phosphorylated in activated neurons ► Immunoprecipitation of pS6 ribosomes enriches for mRNA from activated cells ► Enriched mRNAs reveal molecular identity of neurons activated by nutritional signals ► Dynorphin signaling restrains bouts of intense feeding
Phosphorylation of ribosomal protein S6 correlates with neural activity. The immunoprecipitation of phosphorylated S6 thus enriches for mRNAs that are expressed specifically in activated cells and allows for the identification of neuronal subpopulations that respond to particular stimuli.
Thirst motivates animals to find and consume water. More than 40 years ago, a set of interconnected brain structures known as the lamina terminalis was shown to govern thirst. However, owing to the ...anatomical complexity of these brain regions, the structure and dynamics of their underlying neural circuitry have remained obscure. Recently, the emergence of new tools for neural recording and manipulation has reinvigorated the study of this circuit and prompted re-examination of longstanding questions about the neural origins of thirst. Here, we review these advances, discuss what they teach us about the control of drinking behaviour and outline the key questions that remain unanswered.
In humans and other mammalian species, lesions in the preoptic area of the hypothalamus cause profound sleep impairment, indicating a crucial role of the preoptic area in sleep generation. However, ...the underlying circuit mechanism remains poorly understood. Electrophysiological recordings and c-Fos immunohistochemistry have shown the existence of sleep-active neurons in the preoptic area, especially in the ventrolateral preoptic area and median preoptic nucleus. Pharmacogenetic activation of c-Fos-labelled sleep-active neurons has been shown to induce sleep. However, the sleep-active neurons are spatially intermingled with wake-active neurons, making it difficult to target the sleep neurons specifically for circuit analysis. Here we identify a population of preoptic area sleep neurons on the basis of their projection target and discover their molecular markers. Using a lentivirus expressing channelrhodopsin-2 or a light-activated chloride channel for retrograde labelling, bidirectional optogenetic manipulation, and optrode recording, we show that the preoptic area GABAergic neurons projecting to the tuberomammillary nucleus are both sleep active and sleep promoting. Furthermore, translating ribosome affinity purification and single-cell RNA sequencing identify candidate markers for these neurons, and optogenetic and pharmacogenetic manipulations demonstrate that several peptide markers (cholecystokinin, corticotropin-releasing hormone, and tachykinin 1) label sleep-promoting neurons. Together, these findings provide easy genetic access to sleep-promoting preoptic area neurons and a valuable entry point for dissecting the sleep control circuit.
Communication between the gut and brain is critical for homeostasis, but how this communication is represented in the dynamics of feeding circuits is unknown. Here we describe nutritional regulation ...of key neurons that control hunger in vivo. We show that intragastric nutrient infusion rapidly and durably inhibits hunger-promoting AgRP neurons in awake, behaving mice. This inhibition is proportional to the number of calories infused but surprisingly independent of macronutrient identity or nutritional state. We show that three gastrointestinal signals—serotonin, CCK, and PYY—are necessary or sufficient for these effects. In contrast, the hormone leptin has no acute effect on dynamics of these circuits or their sensory regulation but instead induces a slow modulation that develops over hours and is required for inhibition of feeding. These findings reveal how layers of visceral signals operating on distinct timescales converge on hypothalamic feeding circuits to generate a central representation of energy balance.
•Intragastric nutrients rapidly and durably inhibit hunger-promoting AgRP neurons•AgRP neuron inhibition by nutrients depends on total calories, not nutrient identity•A hormone screen identifies CCK, PYY, and 5HT as post-prandial AgRP neuron regulators•Leptin induces slow modulation of AgRP and POMC neurons on a timescale of hours
Beutler et al. reveal how nutritional signals regulate the hypothalamic hunger circuit. They show that intragastric nutrients inhibit AgRP neurons rapidly in a way dependent solely on calorie content, whereas the satiety hormone leptin only acts on timescale of hours.
The gut is innervated by sensory neurons that relay mechanical and chemical signals to the brain. Two new studies characterize the spinal sensory neurons that innervate the intestines and reveal a ...role for Piezo2 in these cells in sensing colonic distension and regulating gastrointestinal motility.
The gut is innervated by sensory neurons that relay mechanical and chemical signals to the brain. Two new studies characterize the spinal sensory neurons that innervate the intestines and reveal a role for Piezo2 in these cells in sensing colonic distension and regulating gastrointestinal motility.
Thirst motivates animals to drink in order to maintain fluid balance. Thirst has conventionally been viewed as a homeostatic response to changes in blood volume or tonicity. However, most drinking ...behaviour is regulated too rapidly to be controlled by blood composition directly, and instead seems to anticipate homeostatic imbalances before they arise. How this is achieved remains unknown. Here we reveal an unexpected role for the subfornical organ (SFO) in the anticipatory regulation of thirst in mice. By monitoring deep-brain calcium dynamics, we show that thirst-promoting SFO neurons respond to inputs from the oral cavity during eating and drinking and then integrate these inputs with information about the composition of the blood. This integration allows SFO neurons to predict how ongoing food and water consumption will alter fluid balance in the future and then to adjust behaviour pre-emptively. Complementary optogenetic manipulations show that this anticipatory modulation is necessary for drinking in several contexts. These findings provide a neural mechanism to explain longstanding behavioural observations, including the prevalence of drinking during meals, the rapid satiation of thirst, and the fact that oral cooling is thirst-quenching.
AgRP and POMC neurons are two key cell types that regulate feeding in response to hormones and nutrients. Recently, it was discovered that these neurons are also rapidly modulated by the mere sight ...and smell of food. This rapid sensory regulation “resets” the activity of AgRP and POMC neurons before a single bite of food has been consumed. This surprising and counterintuitive discovery challenges longstanding assumptions about the function and regulation of these cells. Here we review these recent findings and discuss their implications for our understanding of feeding behavior. We propose several alternative hypotheses for how these new observations might be integrated into a revised model of the feeding circuit, and also highlight some of the key questions that remain to be answered.
Recent experiments using fiber photometry, microendoscope‐based calcium imaging, and optrode recordings have revealed that arcuate hunger neurons are rapidly modulated by the sensory detection of food. This essay discusses the possible function of this unexpected modulation, including the role of motivation and reinforcement, cephalic phase responses, and anticipatory behavioral transitions.
The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals. These signaling functions are distributed between at least two distinct mTOR ...protein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to the selective inhibitor rapamycin and activated by growth factor stimulation via the canonical phosphoinositide 3-kinase (PI3K)-->Akt-->mTOR pathway. Activated mTORC1 kinase up-regulates protein synthesis by phosphorylating key regulators of mRNA translation. By contrast, mTORC2 is resistant to rapamycin. Genetic studies have suggested that mTORC2 may phosphorylate Akt at S473, one of two phosphorylation sites required for Akt activation; this has been controversial, in part because RNA interference and gene knockouts produce distinct Akt phospho-isoforms. The central role of mTOR in controlling key cellular growth and survival pathways has sparked interest in discovering mTOR inhibitors that bind to the ATP site and therefore target both mTORC2 and mTORC1. We investigated mTOR signaling in cells and animals with two novel and specific mTOR kinase domain inhibitors (TORKinibs). Unlike rapamycin, these TORKinibs (PP242 and PP30) inhibit mTORC2, and we use them to show that pharmacological inhibition of mTOR blocks the phosphorylation of Akt at S473 and prevents its full activation. Furthermore, we show that TORKinibs inhibit proliferation of primary cells more completely than rapamycin. Surprisingly, we find that mTORC2 is not the basis for this enhanced activity, and we show that the TORKinib PP242 is a more effective mTORC1 inhibitor than rapamycin. Importantly, at the molecular level, PP242 inhibits cap-dependent translation under conditions in which rapamycin has no effect. Our findings identify new functional features of mTORC1 that are resistant to rapamycin but are effectively targeted by TORKinibs. These potent new pharmacological agents complement rapamycin in the study of mTOR and its role in normal physiology and human disease.
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