- Email: [email protected]
NO Hemodynamic Speed Limit for Hippocampal Neurogenesis
Neuron
Previews Memo1 function in RGC tiling across evolution? A recent study (Nowakowski et al., 2016) has shown that in human, during cortical development, the radial glia scaffold undergoes transformation into two morphologically and molecularly distinct radial glia subtypes, truncated and outer radial glia. How is the tiling of these distinct RGC types achieved and are the mechanisms conserved? Mutations in human MEMO1 have been found in patients suffering from autism spectrum disorders, implying a relationship between Memo1 loss of function and the etiology of neurodevelopmental disease. It will thus be important to delineate the precise function of MEMO1 in human RGCs for the better understanding of the general mechanisms and also to obtain insights into disease etiology. Altogether, future studies aimed at addressing the above questions will provide a deeper understanding into the mechanisms of how
tiling of RGCs is established and how it contributes to the assembly and function of cortical microcircuits. REFERENCES Beattie, R., Postiglione, M.P., Burnett, L.E., Laukoter, S., Streicher, C., Pauler, F.M., Xiao, G., Klezovitch, O., Vasioukhin, V., Ghashghaei, T.H., and Hippenmeyer, S. (2017). Mosaic analysis with double markers reveals distinct sequential functions of Lgl1 in neural stem cells. Neuron 94, 517–533.e3.
of functionally distinct cell types in the neocortex. Science 358, 610–615. Nakagawa, N., Plestant, C., Yabuno-Nakagawa, K., Li, J., Lee, J., Huang, C.W., Lee, A., Krupa, O., Adhikari, A., Thompson, S., et al. (2019). Memo1-mediated tiling of radial glial cells facilitates cerebral cortical development. Neuron 102, this issue, 836–852. Nowakowski, T.J., Pollen, A.A., SandovalEspinosa, C., and Kriegstein, A.R. (2016). Transformation of the radial glia scaffold demarcates two stages of human cerebral cortex development. Neuron 91, 1219–1227.
Gao, P., Sultan, K.T., Zhang, X.J., and Shi, S.H. (2013). Lineage-dependent circuit assembly in the neocortex. Development 140, 2645–2655.
Rakic, P. (2007). The radial edifice of cortical architecture: from neuronal silhouettes to genetic engineering. Brain Res. Brain Res. Rev. 55, 204–219.
Juric-Sekhar, G., and Hevner, R.F. (2019). Malformations of cerebral cortex development: molecules and mechanisms. Annu. Rev. Pathol. 14, 293–318.
Wester, J.C., Mahadevan, V., Rhodes, C.T., Calvigioni, D., Venkatesh, S., Maric, D., Hunt, S., Yuan, X., Zhang, Y., Petros, T.J., and McBain, C.J. (2019). Neocortical projection neurons instruct inhibitory interneuron circuit development in a lineage-dependent manner. Neuron 102, 960–975.e6.
Li, S., Jin, Z., Koirala, S., Bu, L., Xu, L., Hynes, R.O., Walsh, C.A., Corfas, G., and Piao, X. (2008). GPR56 regulates pial basement membrane integrity and cortical lamination. J. Neurosci. 28, 5817–5826. Maruoka, H., Nakagawa, N., Tsuruno, S., Sakai, S., Yoneda, T., and Hosoya, T. (2017). Lattice system
Wong, F.K., and Marı´n, O. (2019). Developmental cell death in the cerebral cortex. Annu. Rev. Cell Dev. Biol. Published online July 5, 2019. https:// doi.org/10.1146/annurev-cellbio-100818-125204.
NO Hemodynamic Speed Limit for Hippocampal Neurogenesis Jose´ Manuel Morante-Redolat1 and Isabel Farin˜as1,* 1Centro de Investigacio ´ n Biome´dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), and Departamento de Biologı´a Celular, Biologı´a Funcional y Antropologı´a Fı´sica, Universidad de Valencia, 46100 Burjassot, Spain *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2019.08.020
In this issue of Neuron, Shen et al. (2019) address the coupling between vascular flow and neurogenic output, showing that pre-existing hippocampal circuits modulate hemodynamics in a NO-dependent manner to promote IGF-1-dependent survival of newly generated neuroblasts. Behavior and experience modify the brain continuously through a refinement of connections, synapses, and molecular programs that reshapes functional circuitry. Addition of new neurons in the dentate gyrus (DG) of the hippocampal formation represents yet another form of structural and functional neural plasticity. Sustained by life-long persistent neural stem cells (NSCs) in the basal portion of the mature DG granule cell (DGC) layer, unceasing addition of adult-born DGCs constitutes a
fabulous source of adaptive possibilities for hippocampus-based behaviors. In turn, adult hippocampal neurogenesis is regulated by experience, as shown in multiple studies in which animals are exposed to enriched environments (Kempermann et al., 1997). Neurogenic output depends on the activity of NSCs, but also on the survival of the newly generated neuroblasts, as these are produced in large numbers that are later adjusted by apoptosis (Zhao et al., 2008). Novelty boosts neurogenesis
752 Neuron 103, September 4, 2019 ª 2019 Elsevier Inc.
primarily by increasing the survival of newborn DGCs, as can be evidenced by analyzing the proportions of bromodeoxyuridine (BrdU)-labeled cells that remain in the DGC layer a few weeks after administration of the nucleoside. Because the mechanisms involved in the regulation of newborn neuron survival are not completely understood, the Ge lab had already addressed this topic and reported that mature DGCs increase their calcium transient frequency in response to novel,
Neuron
Previews
Figure 1. Pre-existing DG Circuits Regulate the Rate of Neurogenesis through Local Action on Hemodynamics Schematic drawing showing the main findings of the paper by Shen and colleagues as well as the experimental manipulations performed by the authors.
real or virtual, environments and that optogenetic silencing of this activity during the exposure results in reduced survival of new DGCs (Kirschen et al., 2017). In this issue of Neuron, Shen et al., (2019) take a step further and investigate the mechanistic connection between pre-existing DGC activation and newly generated DGC survival. In their previous report, the authors had used a deep-brain endoscopic imaging system to monitor in real time fluorescent emission of calcium-sensor proteins in individual hippocampal neurons of freely moving mice (Kirschen et al., 2017). In the present work, the authors decided to combine optogenetic and pharmacological manipulations with measurements of Ca2+ events, as before, but also with measurements of blood-flow velocity as an ac-
curate indicator of microvascular dilation dynamics (O’Herron et al., 2016). To do so, a gradient refractive index lens probe was stereotaxically implanted 0.2 mm above the DGC layer and connected to a microscope baseplate in mice that had received local injections of adeno-associated viruses (AAVs) carrying constructs for fluorescent reporter or calcium sensor proteins. Fluorescence creates a background illumination in nearby capillaries that allows distinction between red blood cells and plasma due to their differential fluorescent absorption. The sharp contrast in optical signal between cells and fluid can be used to measure movement of blood cells along a microvessel. Using this approach, the authors observed how microvascular blood-flow velocity increases during exploration of an enriched
environment, consisting of a cage with five different objects, relative to an empty home cage with bedding only. Under the enriched conditions, the increase in blood-flow velocity, or hyperemia, in the DG is apparent during the first 10 min of novel object exploration, returns to baseline within approximately 1 h, and appears specific to hippocampus-engaged behaviors as it is not induced by auditory stimulation. Hemodynamic changes in response to specific behaviors suggested a neurovascular coupling and, therefore, the authors focused their attention on a subpopulation of parvalbumin-positive (PV+) GABAergic interneurons that are located close to DG-irrigating vessels and express the neuronal isoform of the nitric oxide (NO) synthase (nNOS). NO is a potent vasodilator, and pharmacological Neuron 103, September 4, 2019 753
Neuron
Previews inhibition of all NOS isoforms, including the neuronal one, by injection of the pan-NOS L-NAME drug prevented behavioral hyperemia in the hippocampus and interfered with the increased exploration-induced survival of newborn DGCs labeled with BrdU. The same result could be achieved by interfering with nNOS specifically using shRNA-carrying AAVs, indicating that the hyperemia induced by neuronal activity was the result of NO signaling (see Figure 1). The authors were ready to interrogate the neural connections potentially involved in linking behavior to this neurovascular interaction. The team next performed a series of elegant, well-controlled, and highly complex manipulations aimed at producing activation or inhibition of all the elements of the proposed circuit by stereotaxic injection of AAVs carrying constructs for designer receptors exclusively activated by designer drugs (DREADDs). Cre recombinase-dependent AAVs carrying either excitatory hM3Dq (Gq) or inhibitory hM4Di DREADDs were delivered locally into the DG of PV-Cre mice that were later injected with the clozapine-N-oxide (CNO) synthetic designer ligand. Activation of PV neurons induced hyperemia and survival of newborn DGCs if production of NO was not inhibited. Complementary results were obtained when the inhibitory DREADD was induced in PV+ neurons with CNO during exploration of enriched environments, demonstrating that these interneurons regulate blood flow during the activity. Introduction of the hM3Dq DREADD under the control of a CaMKII promoter that drives expression in mature DGCs also resulted in CNO-induced hyperemia, and more interestingly, the effect was counteracted when the inhibitory hM4Di receptor was simultaneously activated in PV+ neurons (see Figure 1). The results showing a link between behavior-induced neural activity and gen-
754 Neuron 103, September 4, 2019
eration of new neurons via effects on vascular modulation were already very nice. But the authors decided to address the next question, or how an increase in blood-flow velocity improves newborn DGC survival. Because circulating insulin growth factor 1 (IGF-1) had been shown to increase addition of newborn DGC neurons during exercise, another activity that stimulates hippocampal neurogenesis (Trejo et al., 2001), the authors combined PV activation with the local infusion of picropodophyllin, a mayapple plant alkaloid that selectively blocks IGF-1 receptor phosphorylation. Inhibition of IGF-1 signaling attenuated PV activityinduced newborn DGC survival, indicating its involvement in the neurovascular network that regulates neurogenesis (see Figure 1). The present work by Shen et al. represents an audacious effort to understand the neurovascular regulation of adult neurogenesis in an integrative manner. It also poses other interesting questions for future analyses. Anatomical interactions of adult NSCs and newly generated neurons with capillaries have been extensively described, leading to the concept of the perivascular niche as a microenvironment where elements of the neurogenic lineage would be exposed to specific signaling cues (Goldman and Chen, 2011). Although a number of angiocrine factors produced and released by endothelial cells have been shown to regulate adult neurogenesis (Rafii et al., 2016), there are no reports on whether blood flow indeed affects this process. Interestingly, circulating IGF-1 has been shown to cross the blood-brain barrier in response to neural activity (Nishijima et al., 2010), and rejuvenation of the neurogenesis rate in heterochronic parabiosis experiments also suggests protein transport across the barrier (Smith et al., 2018). If hyperemia can increase the potential
transfer of blood-borne proteins from the systemic milieu to the brain parenchyma in response to neural activity, maybe there is space for a connection between behavior and aging effects. Any answer will require a return to the bench. REFERENCES Goldman, S.A., and Chen, Z. (2011). Perivascular instruction of cell genesis and fate in the adult brain. Nat. Neurosci. 14, 1382–1389. Kempermann, G., Kuhn, H.G., and Gage, F.H. (1997). More hippocampal neurons in adult mice living in an enriched environment. Nature 386, 493–495. Kirschen, G.W., Shen, J., Tian, M., Schroeder, B., Wang, J., Man, G., Wu, S., and Ge, S. (2017). Active dentate granule cells encode experience to promote the addition of adult-born hippocampal neurons. J. Neurosci. 37, 4661–4678. Nishijima, T., Piriz, J., Duflot, S., Fernandez, A.M., Gaitan, G., Gomez-Pinedo, U., Verdugo, J.M., Leroy, F., Soya, H., Nun˜ez, A., and TorresAleman, I. (2010). Neuronal activity drives localized blood-brain-barrier transport of serum insulin-like growth factor-I into the CNS. Neuron 67, 834–846. O’Herron, P., Chhatbar, P.Y., Levy, M., Shen, Z., Schramm, A.E., Lu, Z., and Kara, P. (2016). Neural correlates of single-vessel haemodynamic responses in vivo. Nature 534, 378–382. Rafii, S., Butler, J.M., and Ding, B.S. (2016). Angiocrine functions of organ-specific endothelial cells. Nature 529, 316–325. Shen, J., Wang, D., Wang, X., Gupta, S., Ayloo, B., Wu, S., Prasad, P., Xiong, Q., Xia, J., and Ge, S. (2019). Neurovascular coupling in the dentate gyrus regulates adult hippocampal neurogenesis. Neuron 103, this issue, 878–890. Smith, L.K., White, C.W., 3rd, and Villeda, S.A. (2018). The systemic environment: at the interface of aging and adult neurogenesis. Cell Tissue Res. 371, 105–113. Trejo, J.L., Carro, E., and Torres-Aleman, I. (2001). Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J. Neurosci. 21, 1628–1634. Zhao, C., Deng, W., and Gage, F.H. (2008). Mechanisms and functional implications of adult neurogenesis. Cell 132, 645–660.
Previews Memo1 function in RGC tiling across evolution? A recent study (Nowakowski et al., 2016) has shown that in human, during cortical development, the radial glia scaffold undergoes transformation into two morphologically and molecularly distinct radial glia subtypes, truncated and outer radial glia. How is the tiling of these distinct RGC types achieved and are the mechanisms conserved? Mutations in human MEMO1 have been found in patients suffering from autism spectrum disorders, implying a relationship between Memo1 loss of function and the etiology of neurodevelopmental disease. It will thus be important to delineate the precise function of MEMO1 in human RGCs for the better understanding of the general mechanisms and also to obtain insights into disease etiology. Altogether, future studies aimed at addressing the above questions will provide a deeper understanding into the mechanisms of how
tiling of RGCs is established and how it contributes to the assembly and function of cortical microcircuits. REFERENCES Beattie, R., Postiglione, M.P., Burnett, L.E., Laukoter, S., Streicher, C., Pauler, F.M., Xiao, G., Klezovitch, O., Vasioukhin, V., Ghashghaei, T.H., and Hippenmeyer, S. (2017). Mosaic analysis with double markers reveals distinct sequential functions of Lgl1 in neural stem cells. Neuron 94, 517–533.e3.
of functionally distinct cell types in the neocortex. Science 358, 610–615. Nakagawa, N., Plestant, C., Yabuno-Nakagawa, K., Li, J., Lee, J., Huang, C.W., Lee, A., Krupa, O., Adhikari, A., Thompson, S., et al. (2019). Memo1-mediated tiling of radial glial cells facilitates cerebral cortical development. Neuron 102, this issue, 836–852. Nowakowski, T.J., Pollen, A.A., SandovalEspinosa, C., and Kriegstein, A.R. (2016). Transformation of the radial glia scaffold demarcates two stages of human cerebral cortex development. Neuron 91, 1219–1227.
Gao, P., Sultan, K.T., Zhang, X.J., and Shi, S.H. (2013). Lineage-dependent circuit assembly in the neocortex. Development 140, 2645–2655.
Rakic, P. (2007). The radial edifice of cortical architecture: from neuronal silhouettes to genetic engineering. Brain Res. Brain Res. Rev. 55, 204–219.
Juric-Sekhar, G., and Hevner, R.F. (2019). Malformations of cerebral cortex development: molecules and mechanisms. Annu. Rev. Pathol. 14, 293–318.
Wester, J.C., Mahadevan, V., Rhodes, C.T., Calvigioni, D., Venkatesh, S., Maric, D., Hunt, S., Yuan, X., Zhang, Y., Petros, T.J., and McBain, C.J. (2019). Neocortical projection neurons instruct inhibitory interneuron circuit development in a lineage-dependent manner. Neuron 102, 960–975.e6.
Li, S., Jin, Z., Koirala, S., Bu, L., Xu, L., Hynes, R.O., Walsh, C.A., Corfas, G., and Piao, X. (2008). GPR56 regulates pial basement membrane integrity and cortical lamination. J. Neurosci. 28, 5817–5826. Maruoka, H., Nakagawa, N., Tsuruno, S., Sakai, S., Yoneda, T., and Hosoya, T. (2017). Lattice system
Wong, F.K., and Marı´n, O. (2019). Developmental cell death in the cerebral cortex. Annu. Rev. Cell Dev. Biol. Published online July 5, 2019. https:// doi.org/10.1146/annurev-cellbio-100818-125204.
NO Hemodynamic Speed Limit for Hippocampal Neurogenesis Jose´ Manuel Morante-Redolat1 and Isabel Farin˜as1,* 1Centro de Investigacio ´ n Biome´dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), and Departamento de Biologı´a Celular, Biologı´a Funcional y Antropologı´a Fı´sica, Universidad de Valencia, 46100 Burjassot, Spain *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2019.08.020
In this issue of Neuron, Shen et al. (2019) address the coupling between vascular flow and neurogenic output, showing that pre-existing hippocampal circuits modulate hemodynamics in a NO-dependent manner to promote IGF-1-dependent survival of newly generated neuroblasts. Behavior and experience modify the brain continuously through a refinement of connections, synapses, and molecular programs that reshapes functional circuitry. Addition of new neurons in the dentate gyrus (DG) of the hippocampal formation represents yet another form of structural and functional neural plasticity. Sustained by life-long persistent neural stem cells (NSCs) in the basal portion of the mature DG granule cell (DGC) layer, unceasing addition of adult-born DGCs constitutes a
fabulous source of adaptive possibilities for hippocampus-based behaviors. In turn, adult hippocampal neurogenesis is regulated by experience, as shown in multiple studies in which animals are exposed to enriched environments (Kempermann et al., 1997). Neurogenic output depends on the activity of NSCs, but also on the survival of the newly generated neuroblasts, as these are produced in large numbers that are later adjusted by apoptosis (Zhao et al., 2008). Novelty boosts neurogenesis
752 Neuron 103, September 4, 2019 ª 2019 Elsevier Inc.
primarily by increasing the survival of newborn DGCs, as can be evidenced by analyzing the proportions of bromodeoxyuridine (BrdU)-labeled cells that remain in the DGC layer a few weeks after administration of the nucleoside. Because the mechanisms involved in the regulation of newborn neuron survival are not completely understood, the Ge lab had already addressed this topic and reported that mature DGCs increase their calcium transient frequency in response to novel,
Neuron
Previews
Figure 1. Pre-existing DG Circuits Regulate the Rate of Neurogenesis through Local Action on Hemodynamics Schematic drawing showing the main findings of the paper by Shen and colleagues as well as the experimental manipulations performed by the authors.
real or virtual, environments and that optogenetic silencing of this activity during the exposure results in reduced survival of new DGCs (Kirschen et al., 2017). In this issue of Neuron, Shen et al., (2019) take a step further and investigate the mechanistic connection between pre-existing DGC activation and newly generated DGC survival. In their previous report, the authors had used a deep-brain endoscopic imaging system to monitor in real time fluorescent emission of calcium-sensor proteins in individual hippocampal neurons of freely moving mice (Kirschen et al., 2017). In the present work, the authors decided to combine optogenetic and pharmacological manipulations with measurements of Ca2+ events, as before, but also with measurements of blood-flow velocity as an ac-
curate indicator of microvascular dilation dynamics (O’Herron et al., 2016). To do so, a gradient refractive index lens probe was stereotaxically implanted 0.2 mm above the DGC layer and connected to a microscope baseplate in mice that had received local injections of adeno-associated viruses (AAVs) carrying constructs for fluorescent reporter or calcium sensor proteins. Fluorescence creates a background illumination in nearby capillaries that allows distinction between red blood cells and plasma due to their differential fluorescent absorption. The sharp contrast in optical signal between cells and fluid can be used to measure movement of blood cells along a microvessel. Using this approach, the authors observed how microvascular blood-flow velocity increases during exploration of an enriched
environment, consisting of a cage with five different objects, relative to an empty home cage with bedding only. Under the enriched conditions, the increase in blood-flow velocity, or hyperemia, in the DG is apparent during the first 10 min of novel object exploration, returns to baseline within approximately 1 h, and appears specific to hippocampus-engaged behaviors as it is not induced by auditory stimulation. Hemodynamic changes in response to specific behaviors suggested a neurovascular coupling and, therefore, the authors focused their attention on a subpopulation of parvalbumin-positive (PV+) GABAergic interneurons that are located close to DG-irrigating vessels and express the neuronal isoform of the nitric oxide (NO) synthase (nNOS). NO is a potent vasodilator, and pharmacological Neuron 103, September 4, 2019 753
Neuron
Previews inhibition of all NOS isoforms, including the neuronal one, by injection of the pan-NOS L-NAME drug prevented behavioral hyperemia in the hippocampus and interfered with the increased exploration-induced survival of newborn DGCs labeled with BrdU. The same result could be achieved by interfering with nNOS specifically using shRNA-carrying AAVs, indicating that the hyperemia induced by neuronal activity was the result of NO signaling (see Figure 1). The authors were ready to interrogate the neural connections potentially involved in linking behavior to this neurovascular interaction. The team next performed a series of elegant, well-controlled, and highly complex manipulations aimed at producing activation or inhibition of all the elements of the proposed circuit by stereotaxic injection of AAVs carrying constructs for designer receptors exclusively activated by designer drugs (DREADDs). Cre recombinase-dependent AAVs carrying either excitatory hM3Dq (Gq) or inhibitory hM4Di DREADDs were delivered locally into the DG of PV-Cre mice that were later injected with the clozapine-N-oxide (CNO) synthetic designer ligand. Activation of PV neurons induced hyperemia and survival of newborn DGCs if production of NO was not inhibited. Complementary results were obtained when the inhibitory DREADD was induced in PV+ neurons with CNO during exploration of enriched environments, demonstrating that these interneurons regulate blood flow during the activity. Introduction of the hM3Dq DREADD under the control of a CaMKII promoter that drives expression in mature DGCs also resulted in CNO-induced hyperemia, and more interestingly, the effect was counteracted when the inhibitory hM4Di receptor was simultaneously activated in PV+ neurons (see Figure 1). The results showing a link between behavior-induced neural activity and gen-
754 Neuron 103, September 4, 2019
eration of new neurons via effects on vascular modulation were already very nice. But the authors decided to address the next question, or how an increase in blood-flow velocity improves newborn DGC survival. Because circulating insulin growth factor 1 (IGF-1) had been shown to increase addition of newborn DGC neurons during exercise, another activity that stimulates hippocampal neurogenesis (Trejo et al., 2001), the authors combined PV activation with the local infusion of picropodophyllin, a mayapple plant alkaloid that selectively blocks IGF-1 receptor phosphorylation. Inhibition of IGF-1 signaling attenuated PV activityinduced newborn DGC survival, indicating its involvement in the neurovascular network that regulates neurogenesis (see Figure 1). The present work by Shen et al. represents an audacious effort to understand the neurovascular regulation of adult neurogenesis in an integrative manner. It also poses other interesting questions for future analyses. Anatomical interactions of adult NSCs and newly generated neurons with capillaries have been extensively described, leading to the concept of the perivascular niche as a microenvironment where elements of the neurogenic lineage would be exposed to specific signaling cues (Goldman and Chen, 2011). Although a number of angiocrine factors produced and released by endothelial cells have been shown to regulate adult neurogenesis (Rafii et al., 2016), there are no reports on whether blood flow indeed affects this process. Interestingly, circulating IGF-1 has been shown to cross the blood-brain barrier in response to neural activity (Nishijima et al., 2010), and rejuvenation of the neurogenesis rate in heterochronic parabiosis experiments also suggests protein transport across the barrier (Smith et al., 2018). If hyperemia can increase the potential
transfer of blood-borne proteins from the systemic milieu to the brain parenchyma in response to neural activity, maybe there is space for a connection between behavior and aging effects. Any answer will require a return to the bench. REFERENCES Goldman, S.A., and Chen, Z. (2011). Perivascular instruction of cell genesis and fate in the adult brain. Nat. Neurosci. 14, 1382–1389. Kempermann, G., Kuhn, H.G., and Gage, F.H. (1997). More hippocampal neurons in adult mice living in an enriched environment. Nature 386, 493–495. Kirschen, G.W., Shen, J., Tian, M., Schroeder, B., Wang, J., Man, G., Wu, S., and Ge, S. (2017). Active dentate granule cells encode experience to promote the addition of adult-born hippocampal neurons. J. Neurosci. 37, 4661–4678. Nishijima, T., Piriz, J., Duflot, S., Fernandez, A.M., Gaitan, G., Gomez-Pinedo, U., Verdugo, J.M., Leroy, F., Soya, H., Nun˜ez, A., and TorresAleman, I. (2010). Neuronal activity drives localized blood-brain-barrier transport of serum insulin-like growth factor-I into the CNS. Neuron 67, 834–846. O’Herron, P., Chhatbar, P.Y., Levy, M., Shen, Z., Schramm, A.E., Lu, Z., and Kara, P. (2016). Neural correlates of single-vessel haemodynamic responses in vivo. Nature 534, 378–382. Rafii, S., Butler, J.M., and Ding, B.S. (2016). Angiocrine functions of organ-specific endothelial cells. Nature 529, 316–325. Shen, J., Wang, D., Wang, X., Gupta, S., Ayloo, B., Wu, S., Prasad, P., Xiong, Q., Xia, J., and Ge, S. (2019). Neurovascular coupling in the dentate gyrus regulates adult hippocampal neurogenesis. Neuron 103, this issue, 878–890. Smith, L.K., White, C.W., 3rd, and Villeda, S.A. (2018). The systemic environment: at the interface of aging and adult neurogenesis. Cell Tissue Res. 371, 105–113. Trejo, J.L., Carro, E., and Torres-Aleman, I. (2001). Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J. Neurosci. 21, 1628–1634. Zhao, C., Deng, W., and Gage, F.H. (2008). Mechanisms and functional implications of adult neurogenesis. Cell 132, 645–660.