Current Biology
Dispatches 13. Booth, W., and Schuett, G.W. (2016). The emerging phylogenetic pattern of parthenogenesis in snakes. Biol. J. Linn. Soc. 118, 172–186.
16. Mallery, C.S., Jr. (2014). Following the chromosomes of inheritance and sex-linkage: an explanation of coral glow/banana. In The Ultimate Ball Python: Morph Maker Guide.
14. Mallery, C.S., Jr., and Carrillo, M.M. (2016). A case study of sex-linkage in Python regius (Serpentes: Boidae), with new insights into sex determination in Henophidia. Phyllomedusa. J. Herpetol. 15, 29–42.
17. Gamble, T. (2016). Using RAD-seq to recognize sex-specific markers and sex chromosome systems. Mol. Ecol. 25, 2114– 2116.
15. Booth, W., Johnson, D.H., Moore, S., Schal, C., and Vargo, E.L. (2010). Evidence for viable, non-clonal but fatherless Boa constrictors. Biol. Lett., rsbl20100793.
18. Bradnam, K.R., Fass, J.N., Alexandrov, A., Baranay, P., Bechner, M., Birol, I., Boisvert, S., Chapman, J.A., Chapuis, G., Chikhi, R., et al. (2013). Assemblathon 2: evaluating de novo
methods of genome assembly in three vertebrate species. GigaScience 2, 10. 19. Castoe, T.A., de Koning, A.P.J., Hall, K.T., Card, D.C., Schield, D.R., Fujita, M.K., Ruggiero, R.P., Degner, J.F., Daza, J.M., Gu, W., et al. (2013). The Burmese python genome reveals the molecular basis for extreme adaptation in snakes. Proc. Natl. Acad. Sci. USA 110, 20645–20650. 20. Ezaz, T., Stiglec, R., Veyrunes, F., and Marshall Graves, J.A. (2006). Relationships between vertebrate ZW and XY sex chromosome systems. Curr. Biol. 16, R736–R743.
Energy Balance: Lateral Hypothalamus Hoards Food Memories Kavya Devarakonda and Paul J. Kenny* Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cub.2017.06.082
The lateral hypothalamus is known to drive food consumption during periods of hunger. A new study suggests that the lateral hypothalamus may also participate in the formation and storage of memories about events in the environment that predict the availability of food. One of the most important functions of the brain is to coordinate behavioral output during periods of hunger to obtain and consume food, thereby replenishing otherwise depleted energy stores to avoid starvation. Frequently, food is not readily available to hungry animals (including humans) for consumption and instead they must successfully forage. Hence, it is critical that an organism learns to recognize cues in the environment that predict food availability, and to use this information during periods of hunger to procure food. Precisely how foodpredictive information in the environment is encoded in the brain is unclear. In a paper published recently in Current Biology, Sharpe et al. [1] present new findings suggesting that neurons in the lateral hypothalamus, previously thought to simply initiate feeding behaviors in hungry animals, are directly involved in learning about food-predictive environmental stimuli that guide foraging behaviors. Nuclei in the hypothalamus play critical roles in feeding behavior. In particular, the lateral hypothalamus is considered a
major feeding center in the brain [2]. Activity of neurons in the lateral hypothalamus is increased during feeding behavior [3]. Moreover, classic electrical brain stimulation experiments have shown that activation of the lateral hypothalamus can trigger voracious eating in animals even when they are fully fed [4,5]. Conversely, lesions of this brain structure result in markedly decreased food consumption and starvation [6]. Using modern tools to target genetically defined populations of neurons, it was recently shown that GABAergic neurons are the major class of cells in the lateral hypothalamus that stimulate feeding behaviors [7,8]. Based on these and related findings, the lateral hypothalamus is generally thought to serve as an ‘actuator’ of feeding behavior that links hunger signals to the initiation of the motor programs that support food-taking behaviors. In their new paper, Sharpe et al. [1] offer a new perspective on the function of the lateral hypothalamus. The authors speculated that feeding-relevant GABAergic neurons in the lateral
hypothalamus may serve as more than simple actuators of feeding behavior: instead, they hypothesized that these cells play an active role in the complex processes by which an organism learns about stimuli in the environment that predict the availability of food. To test their hypothesis, the authors first used bacterial artificial chromosome (BAC) technology to generate a new line of genetically modified rats in which Cre recombinase is expressed under the control of the promoter for the glutamate decarboxylase 1 gene (Gad1-Cre rats). In these rats, the recombinase protein Cre is expressed with high fidelity in GABAergic neurons in the lateral hypothalamus, but is not detected in surrounding orexin or melaninconcentrating hormone (MCH) neurons. This new line of Gad1-Cre rats enabled the authors to manipulate the activity of GABAergic neurons in the lateral hypothalamus and explore their contribution to food-related new learning. Next, Sharpe et al. [1] designed a behavioral task in which Gad1-Cre rats learned to discriminate between two
Current Biology 27, R796–R815, August 21, 2017 ª 2017 Elsevier Ltd. R803
Current Biology
Dispatches different sounds. The animals learned that delivery of sucrose rewards occurred reliably when a particular tone (conditioned stimulus, CS+) was activated but not when the different sound (CS–) was activated. As a consequence, the rats spent more time in the area of the test apparatus where sucrose rewards were delivered (food zone) in the presence of CS+ compared with CS–, confirming that they had successfully learned the association between the CS+ and the imminent delivery of food rewards. Using this behavioral procedure, Sharpe et al. [1] investigated the contribution of GABAergic neurons in the lateral hypothalamus in establishing the association between the CS+ and the availability of food rewards. To accomplish this, they injected a virus that expresses the inhibitory opsin halorhodopsin in a Cre-dependent manner into the lateral hypothalamus of Gad1-Cre rats, resulting in halorhodopsin expression restricted to lateral hypothalamic GABAergic neurons. Stimulating halorhodopsin by means of an implanted optical fiber inhibited the activity of local GABAergic neurons. Inhibiting the GABAergic during CS+ and CS– presentation abolished the ability of the animals to successfully associate the CS+ with food availability, reflected by the fact that they did not spend any more time in the food zone during presentation of CS+ than CS–. When inhibition of the GABAergic neurons was terminated, the animals moved into the food zone in response to the delivery of sucrose rewards, suggesting that inhibiting these cells did not induce long-lasting suppression of food-seeking behaviors. Interestingly, when the same rats were again tested in the presence of the CS+, but in this case without optical inhibition of GABAergic neurons, the animals once again failed to spend increased time in the food zone when the CS+ was presented. This suggests that, rather than inducing statedependent deficits in behavioral performance or transient reductions in the incentive value of the CS+, inhibition of the GABAergic neurons during conditioning instead blocked the ability of the animals to learn about the relationship between CS+ and imminent delivery of food rewards.
Next, Sharpe et al. [1] investigated whether GABAergic neurons in the lateral hypothalamus specifically regulate encoding of information about environmental cues that predict food availability or also regulate the utilization of this information. To accomplish this, animals were first taught to associate the CS+ with food availability. Once this association was established, reflected by increased time spent in the food zone in the presence of the CS+, the effects of optically inhibiting GABAergic neurons in the lateral hypothalamus were again examined. The authors found that inhibiting GABAergic neurons disrupted CS+-stimulated increases in time spent in the food zone in animals that had already successfully learned this response. This suggests that GABAergic neurons in the lateral hypothalamus regulate not just the acquisition of new food-predictive learning about environmental stimuli but also control the ability of animals to use this new information. Finally, Sharpe et al. [1] investigated the broader circuitry through which cuecontrolled food-seeking behavior may be regulated. GABAergic neurons in the lateral hypothalamus are known to project to the ventral tegmental area (VTA), where they regulate the activity of local dopaminergic and nondopaminergic neurons [9,10]. Neurons in the VTA respond to unanticipated rewarding or punishing events to generate ‘teaching signals’ that influence the activity of other brain regions and thereby help to guide future behaviors that facilitate obtaining rewards or avoiding punishments. Strikingly, optical inhibition of the terminals of lateral hypothalamic GABAergic neurons in the VTA enhanced the amount of time that animals spent in the food zone in response to the CS+, the opposite outcome of when the cell bodies of these neurons in the lateral hypothalamus were inhibited. This effect persisted in subsequent trials even when the optical inhibition was no longer delivered, consistent with enhanced learning about the incentive value of the CS+. The mechanisms by which this facilitated learning occurs is unclear. But the results suggest that inhibition of inputs from lateral hypothalamic GABAergic to the VTA enhances the ability of the VTA to generate ‘teaching’ signals that guide food-seeking behaviors.
R804 Current Biology 27, R796–R815, August 21, 2017
The new findings of Sharpe et al. [1] reveal unexpectedly complex functions for GABAergic neurons in the lateral hypothalamus. These cells are not just actuators of feeding behavior but may actively participate in the encoding and utilization of information in the environment that predicts the availability of food. These intriguing findings are consistent with other recent reports that hint at more complex functions of the lateral hypothalamus than previously suspected. For example, while lateral hypothalamus neurons provide a major source of input to the VTA, the VTA in turn projects back to the lateral hypothalamus [9], resulting in a LH/VTA/LH loop (where LH = lateral hypothalamus) [9]. The hypothalamic neurons that comprise the initial LH/VTA portion of this loop were recently shown to increase their activity when animals enter a food delivery zone in response to rewardpredictive environmental stimuli [9]. This observation is consistent with the work of Sharpe et al. [1] as it suggests that the lateral hypothalamus helps to guide foraging behaviors based on events in the environment. By contrast, hypothalamic neurons that comprise the latter VTA/LH portion of this loop are not activated by cue-directed entry to a food delivery zone [9]. Instead, these neurons are activated by the unexpected delivery of food rewards and inhibited by the unexpected omission of predicted food rewards [9]. This suggests that the VTA sends information back to lateral hypothalamus that helps to ‘teach’ this structure about new opportunities for food rewards in the environment and to update established expectations based on new outcomes. Together, these findings suggest that the lateral hypothalamus and VTA act in synchrony to guide foraging and to monitor the successful outcome, or not, of this behavior to optimize future foraging. In summary, the findings of Sharpe et al. [1] reveal an unexpectedly complex role for the lateral hypothalamus in learning about food-predictive cues in the environment and utilization of this information to guide foraging behaviors. These findings are likely to catalyze new investigations into the role of this brain region in maladaptive learning processes that may contribute to over- or
Current Biology
Dispatches under-eating in obese and anorexic individuals, respectively.
REFERENCES 1. Sharpe, M.J., Marchant, N.J., Whitaker, L.R., Richie, C.T., Zhang, Y.J., Campbell, E.J., Koivula, P.P., Necarsulmer, J.C., MejiasAponte, C., Morales, M., et al. (2017). Lateral hypothalamic GABAergic neurons encode reward predictions that are relayed to the ventral tegmental area to regulate learning. Curr. Biol. 27, 2089–2100. 2. Stuber, G.D., and Wise, R.A. (2016). Lateral hypothalamic circuits for feeding and reward. Nat. Neurosci. 19, 198–205. 3. Johnstone, L.E., Fong, T.M., and Leng, G. (2006). Neuronal activation in the
hypothalamus and brainstem during feeding in rats. Cell. Metab. 4, 313–321. 4. Morgane, P.J. (1961). Distinct ‘‘feeding’’ and ‘‘hunger motivating’’ systems in the lateral hypothalamus of the rat. Science 133, 887–888. 5. Herberg, L.J., and Blundell, J.E. (1967). Lateral hypothalamus: hoarding behavior elicited by electrical stimulation. Science 155, 349–350. 6. Anand, B.K., and Brobeck, J.R. (1951). Localization of a ‘‘feeding center’’ in the hypothalamus of the rat. Proc. Soc. Exp. Biol. Med. 77, 323–324. 7. Jennings, J.H., Rizzi, G., Stamatakis, A.M., Ung, R.L., and Stuber, G.D. (2013). The inhibitory circuit architecture of the lateral hypothalamus orchestrates feeding. Science 341, 1517–1521.
8. Jennings, J.H., Ung, R.L., Resendez, S.L., Stamatakis, A.M., Taylor, J.G., Huang, J., Veleta, K., Kantak, P.A., Aita, M., ShillingScrivo, K., et al. (2015). Visualizing hypothalamic network dynamics for appetitive and consummatory behaviors. Cell 160, 516–527. 9. Nieh, E.H., Matthews, G.A., Allsop, S.A., Presbrey, K.N., Leppla, C.A., Wichmann, R., Neve, R., Wildes, C.P., and Tye, K.M. (2015). Decoding neural circuits that control compulsive sucrose seeking. Cell 160, 528–541. 10. Leinninger, G.M., Jo, Y.H., Leshan, R.L., Louis, G.W., Yang, H., Barrera, J.G., Wilson, H., Opland, D.M., Faouzi, M.A., Gong, Y., et al. (2009). Leptin acts via leptin receptorexpressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding. Cell. Metab. 10, 89–98.
Cancer Biology: APC Delivers Kiss of Death to Focal Adhesions €thke Inke Na Cell & Developmental Biology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK Correspondence: [email protected] http://dx.doi.org/10.1016/j.cub.2017.07.028
New work shows that the actin-nucleating ability of the adenomatous polyposis coli protein is required for disassembly of focal adhesions. Loss of this function in Apc mutant cells reduces directed cell migration, potentially explaining the decreased migration of colon cancer cells. Usually, tumor suppressors are associated with signaling pathways that directly affect transcription and gene expression profiles to increase proliferation and survival. The major tumor suppressor in colon cancer — adenomatous polyposis coli (APC) — is unusual in this regard, as it has many different functions and is increasingly recognized as an important cytoskeletal regulator. A new study by Bruce Goode’s team at Brandeis University provides new mechanistic insights into this role and its importance for epithelial cell behavior, particularly directed cell migration and the associated turnover of focal adhesions [1]. The Apc gene is mutated in most tumors of the lining of the intestinal tract and these mutations occur at the earliest stages of cancer initiation [2,3]. The APC protein has received much attention in the
context of regulating the activity of Wnt signaling, which dominates decisions about proliferation in the colonic epithelium and is particularly important for stem cells and their survival [4]. However, unlike other tumor suppressors, APC is also physically linked to many other cellular machineries. Most notably, it has direct interactions with cytoskeletal proteins and some of their regulators [5]. The large molecular size of APC — 2,843 amino acids in humans — and the complexity of its interactions have made it difficult to separate its involvement in Wnt signaling and cytoskeletal regulation [5]. Nonetheless, the consequences of APC–cytoskeleton interactions for cell behavior and the role of changes in these interactions following mutation of Apc in cancer are best understood in the context of the effects on microtubules [6,7]. APC binds to and bundles microtubules and
this contributes to the regulation of normal mitotic spindles and cell migration [6,8]. Importantly, the interaction of APC with microtubules is mutually exclusive with its binding to the Wnt signaling target b-catenin [9,10]. This means that not only truncation mutations in Apc that abolish its binding to microtubules but also stabilizing mutations in b-catenin can inhibit APC-mediated control of microtubule stability and function [9,10]. APC also interacts and cooperates with other microtubule plus-end tracking proteins (+TIPs) to form a superstructure that promotes the polymerization of microtubules [11]. In addition, APC binds to actin and initial studies showed that the same domain that binds directly to microtubules is involved in the binding and bundling of F-actin [12]. In the new study, Juanes et al. [1] examined the functional consequences
Current Biology 27, R796–R815, August 21, 2017 ª 2017 Elsevier Ltd. R805
Dispatches 13. Booth, W., and Schuett, G.W. (2016). The emerging phylogenetic pattern of parthenogenesis in snakes. Biol. J. Linn. Soc. 118, 172–186.
16. Mallery, C.S., Jr. (2014). Following the chromosomes of inheritance and sex-linkage: an explanation of coral glow/banana. In The Ultimate Ball Python: Morph Maker Guide.
14. Mallery, C.S., Jr., and Carrillo, M.M. (2016). A case study of sex-linkage in Python regius (Serpentes: Boidae), with new insights into sex determination in Henophidia. Phyllomedusa. J. Herpetol. 15, 29–42.
17. Gamble, T. (2016). Using RAD-seq to recognize sex-specific markers and sex chromosome systems. Mol. Ecol. 25, 2114– 2116.
15. Booth, W., Johnson, D.H., Moore, S., Schal, C., and Vargo, E.L. (2010). Evidence for viable, non-clonal but fatherless Boa constrictors. Biol. Lett., rsbl20100793.
18. Bradnam, K.R., Fass, J.N., Alexandrov, A., Baranay, P., Bechner, M., Birol, I., Boisvert, S., Chapman, J.A., Chapuis, G., Chikhi, R., et al. (2013). Assemblathon 2: evaluating de novo
methods of genome assembly in three vertebrate species. GigaScience 2, 10. 19. Castoe, T.A., de Koning, A.P.J., Hall, K.T., Card, D.C., Schield, D.R., Fujita, M.K., Ruggiero, R.P., Degner, J.F., Daza, J.M., Gu, W., et al. (2013). The Burmese python genome reveals the molecular basis for extreme adaptation in snakes. Proc. Natl. Acad. Sci. USA 110, 20645–20650. 20. Ezaz, T., Stiglec, R., Veyrunes, F., and Marshall Graves, J.A. (2006). Relationships between vertebrate ZW and XY sex chromosome systems. Curr. Biol. 16, R736–R743.
Energy Balance: Lateral Hypothalamus Hoards Food Memories Kavya Devarakonda and Paul J. Kenny* Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cub.2017.06.082
The lateral hypothalamus is known to drive food consumption during periods of hunger. A new study suggests that the lateral hypothalamus may also participate in the formation and storage of memories about events in the environment that predict the availability of food. One of the most important functions of the brain is to coordinate behavioral output during periods of hunger to obtain and consume food, thereby replenishing otherwise depleted energy stores to avoid starvation. Frequently, food is not readily available to hungry animals (including humans) for consumption and instead they must successfully forage. Hence, it is critical that an organism learns to recognize cues in the environment that predict food availability, and to use this information during periods of hunger to procure food. Precisely how foodpredictive information in the environment is encoded in the brain is unclear. In a paper published recently in Current Biology, Sharpe et al. [1] present new findings suggesting that neurons in the lateral hypothalamus, previously thought to simply initiate feeding behaviors in hungry animals, are directly involved in learning about food-predictive environmental stimuli that guide foraging behaviors. Nuclei in the hypothalamus play critical roles in feeding behavior. In particular, the lateral hypothalamus is considered a
major feeding center in the brain [2]. Activity of neurons in the lateral hypothalamus is increased during feeding behavior [3]. Moreover, classic electrical brain stimulation experiments have shown that activation of the lateral hypothalamus can trigger voracious eating in animals even when they are fully fed [4,5]. Conversely, lesions of this brain structure result in markedly decreased food consumption and starvation [6]. Using modern tools to target genetically defined populations of neurons, it was recently shown that GABAergic neurons are the major class of cells in the lateral hypothalamus that stimulate feeding behaviors [7,8]. Based on these and related findings, the lateral hypothalamus is generally thought to serve as an ‘actuator’ of feeding behavior that links hunger signals to the initiation of the motor programs that support food-taking behaviors. In their new paper, Sharpe et al. [1] offer a new perspective on the function of the lateral hypothalamus. The authors speculated that feeding-relevant GABAergic neurons in the lateral
hypothalamus may serve as more than simple actuators of feeding behavior: instead, they hypothesized that these cells play an active role in the complex processes by which an organism learns about stimuli in the environment that predict the availability of food. To test their hypothesis, the authors first used bacterial artificial chromosome (BAC) technology to generate a new line of genetically modified rats in which Cre recombinase is expressed under the control of the promoter for the glutamate decarboxylase 1 gene (Gad1-Cre rats). In these rats, the recombinase protein Cre is expressed with high fidelity in GABAergic neurons in the lateral hypothalamus, but is not detected in surrounding orexin or melaninconcentrating hormone (MCH) neurons. This new line of Gad1-Cre rats enabled the authors to manipulate the activity of GABAergic neurons in the lateral hypothalamus and explore their contribution to food-related new learning. Next, Sharpe et al. [1] designed a behavioral task in which Gad1-Cre rats learned to discriminate between two
Current Biology 27, R796–R815, August 21, 2017 ª 2017 Elsevier Ltd. R803
Current Biology
Dispatches different sounds. The animals learned that delivery of sucrose rewards occurred reliably when a particular tone (conditioned stimulus, CS+) was activated but not when the different sound (CS–) was activated. As a consequence, the rats spent more time in the area of the test apparatus where sucrose rewards were delivered (food zone) in the presence of CS+ compared with CS–, confirming that they had successfully learned the association between the CS+ and the imminent delivery of food rewards. Using this behavioral procedure, Sharpe et al. [1] investigated the contribution of GABAergic neurons in the lateral hypothalamus in establishing the association between the CS+ and the availability of food rewards. To accomplish this, they injected a virus that expresses the inhibitory opsin halorhodopsin in a Cre-dependent manner into the lateral hypothalamus of Gad1-Cre rats, resulting in halorhodopsin expression restricted to lateral hypothalamic GABAergic neurons. Stimulating halorhodopsin by means of an implanted optical fiber inhibited the activity of local GABAergic neurons. Inhibiting the GABAergic during CS+ and CS– presentation abolished the ability of the animals to successfully associate the CS+ with food availability, reflected by the fact that they did not spend any more time in the food zone during presentation of CS+ than CS–. When inhibition of the GABAergic neurons was terminated, the animals moved into the food zone in response to the delivery of sucrose rewards, suggesting that inhibiting these cells did not induce long-lasting suppression of food-seeking behaviors. Interestingly, when the same rats were again tested in the presence of the CS+, but in this case without optical inhibition of GABAergic neurons, the animals once again failed to spend increased time in the food zone when the CS+ was presented. This suggests that, rather than inducing statedependent deficits in behavioral performance or transient reductions in the incentive value of the CS+, inhibition of the GABAergic neurons during conditioning instead blocked the ability of the animals to learn about the relationship between CS+ and imminent delivery of food rewards.
Next, Sharpe et al. [1] investigated whether GABAergic neurons in the lateral hypothalamus specifically regulate encoding of information about environmental cues that predict food availability or also regulate the utilization of this information. To accomplish this, animals were first taught to associate the CS+ with food availability. Once this association was established, reflected by increased time spent in the food zone in the presence of the CS+, the effects of optically inhibiting GABAergic neurons in the lateral hypothalamus were again examined. The authors found that inhibiting GABAergic neurons disrupted CS+-stimulated increases in time spent in the food zone in animals that had already successfully learned this response. This suggests that GABAergic neurons in the lateral hypothalamus regulate not just the acquisition of new food-predictive learning about environmental stimuli but also control the ability of animals to use this new information. Finally, Sharpe et al. [1] investigated the broader circuitry through which cuecontrolled food-seeking behavior may be regulated. GABAergic neurons in the lateral hypothalamus are known to project to the ventral tegmental area (VTA), where they regulate the activity of local dopaminergic and nondopaminergic neurons [9,10]. Neurons in the VTA respond to unanticipated rewarding or punishing events to generate ‘teaching signals’ that influence the activity of other brain regions and thereby help to guide future behaviors that facilitate obtaining rewards or avoiding punishments. Strikingly, optical inhibition of the terminals of lateral hypothalamic GABAergic neurons in the VTA enhanced the amount of time that animals spent in the food zone in response to the CS+, the opposite outcome of when the cell bodies of these neurons in the lateral hypothalamus were inhibited. This effect persisted in subsequent trials even when the optical inhibition was no longer delivered, consistent with enhanced learning about the incentive value of the CS+. The mechanisms by which this facilitated learning occurs is unclear. But the results suggest that inhibition of inputs from lateral hypothalamic GABAergic to the VTA enhances the ability of the VTA to generate ‘teaching’ signals that guide food-seeking behaviors.
R804 Current Biology 27, R796–R815, August 21, 2017
The new findings of Sharpe et al. [1] reveal unexpectedly complex functions for GABAergic neurons in the lateral hypothalamus. These cells are not just actuators of feeding behavior but may actively participate in the encoding and utilization of information in the environment that predicts the availability of food. These intriguing findings are consistent with other recent reports that hint at more complex functions of the lateral hypothalamus than previously suspected. For example, while lateral hypothalamus neurons provide a major source of input to the VTA, the VTA in turn projects back to the lateral hypothalamus [9], resulting in a LH/VTA/LH loop (where LH = lateral hypothalamus) [9]. The hypothalamic neurons that comprise the initial LH/VTA portion of this loop were recently shown to increase their activity when animals enter a food delivery zone in response to rewardpredictive environmental stimuli [9]. This observation is consistent with the work of Sharpe et al. [1] as it suggests that the lateral hypothalamus helps to guide foraging behaviors based on events in the environment. By contrast, hypothalamic neurons that comprise the latter VTA/LH portion of this loop are not activated by cue-directed entry to a food delivery zone [9]. Instead, these neurons are activated by the unexpected delivery of food rewards and inhibited by the unexpected omission of predicted food rewards [9]. This suggests that the VTA sends information back to lateral hypothalamus that helps to ‘teach’ this structure about new opportunities for food rewards in the environment and to update established expectations based on new outcomes. Together, these findings suggest that the lateral hypothalamus and VTA act in synchrony to guide foraging and to monitor the successful outcome, or not, of this behavior to optimize future foraging. In summary, the findings of Sharpe et al. [1] reveal an unexpectedly complex role for the lateral hypothalamus in learning about food-predictive cues in the environment and utilization of this information to guide foraging behaviors. These findings are likely to catalyze new investigations into the role of this brain region in maladaptive learning processes that may contribute to over- or
Current Biology
Dispatches under-eating in obese and anorexic individuals, respectively.
REFERENCES 1. Sharpe, M.J., Marchant, N.J., Whitaker, L.R., Richie, C.T., Zhang, Y.J., Campbell, E.J., Koivula, P.P., Necarsulmer, J.C., MejiasAponte, C., Morales, M., et al. (2017). Lateral hypothalamic GABAergic neurons encode reward predictions that are relayed to the ventral tegmental area to regulate learning. Curr. Biol. 27, 2089–2100. 2. Stuber, G.D., and Wise, R.A. (2016). Lateral hypothalamic circuits for feeding and reward. Nat. Neurosci. 19, 198–205. 3. Johnstone, L.E., Fong, T.M., and Leng, G. (2006). Neuronal activation in the
hypothalamus and brainstem during feeding in rats. Cell. Metab. 4, 313–321. 4. Morgane, P.J. (1961). Distinct ‘‘feeding’’ and ‘‘hunger motivating’’ systems in the lateral hypothalamus of the rat. Science 133, 887–888. 5. Herberg, L.J., and Blundell, J.E. (1967). Lateral hypothalamus: hoarding behavior elicited by electrical stimulation. Science 155, 349–350. 6. Anand, B.K., and Brobeck, J.R. (1951). Localization of a ‘‘feeding center’’ in the hypothalamus of the rat. Proc. Soc. Exp. Biol. Med. 77, 323–324. 7. Jennings, J.H., Rizzi, G., Stamatakis, A.M., Ung, R.L., and Stuber, G.D. (2013). The inhibitory circuit architecture of the lateral hypothalamus orchestrates feeding. Science 341, 1517–1521.
8. Jennings, J.H., Ung, R.L., Resendez, S.L., Stamatakis, A.M., Taylor, J.G., Huang, J., Veleta, K., Kantak, P.A., Aita, M., ShillingScrivo, K., et al. (2015). Visualizing hypothalamic network dynamics for appetitive and consummatory behaviors. Cell 160, 516–527. 9. Nieh, E.H., Matthews, G.A., Allsop, S.A., Presbrey, K.N., Leppla, C.A., Wichmann, R., Neve, R., Wildes, C.P., and Tye, K.M. (2015). Decoding neural circuits that control compulsive sucrose seeking. Cell 160, 528–541. 10. Leinninger, G.M., Jo, Y.H., Leshan, R.L., Louis, G.W., Yang, H., Barrera, J.G., Wilson, H., Opland, D.M., Faouzi, M.A., Gong, Y., et al. (2009). Leptin acts via leptin receptorexpressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding. Cell. Metab. 10, 89–98.
Cancer Biology: APC Delivers Kiss of Death to Focal Adhesions €thke Inke Na Cell & Developmental Biology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK Correspondence: [email protected] http://dx.doi.org/10.1016/j.cub.2017.07.028
New work shows that the actin-nucleating ability of the adenomatous polyposis coli protein is required for disassembly of focal adhesions. Loss of this function in Apc mutant cells reduces directed cell migration, potentially explaining the decreased migration of colon cancer cells. Usually, tumor suppressors are associated with signaling pathways that directly affect transcription and gene expression profiles to increase proliferation and survival. The major tumor suppressor in colon cancer — adenomatous polyposis coli (APC) — is unusual in this regard, as it has many different functions and is increasingly recognized as an important cytoskeletal regulator. A new study by Bruce Goode’s team at Brandeis University provides new mechanistic insights into this role and its importance for epithelial cell behavior, particularly directed cell migration and the associated turnover of focal adhesions [1]. The Apc gene is mutated in most tumors of the lining of the intestinal tract and these mutations occur at the earliest stages of cancer initiation [2,3]. The APC protein has received much attention in the
context of regulating the activity of Wnt signaling, which dominates decisions about proliferation in the colonic epithelium and is particularly important for stem cells and their survival [4]. However, unlike other tumor suppressors, APC is also physically linked to many other cellular machineries. Most notably, it has direct interactions with cytoskeletal proteins and some of their regulators [5]. The large molecular size of APC — 2,843 amino acids in humans — and the complexity of its interactions have made it difficult to separate its involvement in Wnt signaling and cytoskeletal regulation [5]. Nonetheless, the consequences of APC–cytoskeleton interactions for cell behavior and the role of changes in these interactions following mutation of Apc in cancer are best understood in the context of the effects on microtubules [6,7]. APC binds to and bundles microtubules and
this contributes to the regulation of normal mitotic spindles and cell migration [6,8]. Importantly, the interaction of APC with microtubules is mutually exclusive with its binding to the Wnt signaling target b-catenin [9,10]. This means that not only truncation mutations in Apc that abolish its binding to microtubules but also stabilizing mutations in b-catenin can inhibit APC-mediated control of microtubule stability and function [9,10]. APC also interacts and cooperates with other microtubule plus-end tracking proteins (+TIPs) to form a superstructure that promotes the polymerization of microtubules [11]. In addition, APC binds to actin and initial studies showed that the same domain that binds directly to microtubules is involved in the binding and bundling of F-actin [12]. In the new study, Juanes et al. [1] examined the functional consequences
Current Biology 27, R796–R815, August 21, 2017 ª 2017 Elsevier Ltd. R805
