- Email: [email protected]
The Birth of the Barrels
Developmental Cell
Previews The Birth of the Barrels Patricia Gaspar1,2,* and Reha Erzurumlu3 1INSERM
UMR-S 839, Universite´ Pierre et Marie Curie, 75005 Paris, France du Fer a` Moulin, 17 rue du Fer a` Moulin, 75005 Paris, France 3Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.devcel.2013.09.028 2Institut
Refinement of sensory maps follows a highly reproducible tempo dictated largely by peripheral sensory receptors and neural activity. In this issue of Developmental Cell, Toda et al. (2013) add a new twist by showing that the timing of birth plays a decisive role in setting the clock for pattern emergence. It makes perfect sense that the time spent in utero has different effects on the brain as compared to development after birth, when the newborn animal needs to rapidly adapt to its new sensory environment. However, testing the specific role of birth in neuronal development is difficult. Procedures that cause premature delivery in mice, such as hormonal changes or Caesarean extraction of embryos, are likely to have nonspecific and difficult-to-control effects such as decreased body weight and modified maternal behavior. Furthermore, the precise recording of birth dates and of neuronal maturation events can be a hurdle. This latter issue, however, can be overcome by taking advantage of neuronal pathways with stereotyped development. The somatosensory pathway, which originates in the whiskers and terminates in cortical structures known as barrels, and the eye-specific organization of retinal inputs in the lateral geniculate nucleus (the primary sensory relay of visual inputs) are two such pathways that have precise and well-described sequences of maturation. Previous studies have indicated the presence of some variability in the date of emergence of barrel patterns in the rodent somatosensory cortex in relation to the nutritional status and body weight of pups, but generally these studies saw delayed maturation due to malnutrition (Vongdokmai, 1980; Medina-Aguirre et al., 2008) or lower body weight (Hoerder-Suabedissen et al., 2008). In this issue of Developmental Cell, Toda et al. (2013) add a new twist on the usual temporal sequence of sensory map refinement by the peripheral sensory receptors and neural activity (Erzurumlu and Gaspar, 2012; Huberman et al.,
2008) by showing that the timing of birth plays a decisive role in setting the clock for neural circuit connectivity and pattern emergence. The authors examined the effects of premature birth on barrel patterning by inducing preterm delivery in three different ways: administration of mifepristone, a progesterone antagonist that causes premature delivery; ovariectomy, which also causes premature delivery; and Caesarian extraction. Although each of these approaches can have its own pitfalls, great care was taken to introduce the appropriate controls for each experimental paradigm. Strikingly, all three experimental conditions led to a one-day advance in the emergence of barrel patterns in the somatosensory cortex relative to the date of conception. In other words, this study indicates that barrel patterns emerge at a fixed date after birth, regardless of whether the animals were born prematurely. This is quite remarkable because the timing for patterning in the lower relay stations such as the thalamus or brainstem trigeminal relays is unchanged, being set to the date of conception rather than the date of birth. Indeed, the critical period for lesion-induced plasticity, which is known to depend on these lower sensory relays (Erzurumlu and Gaspar 2012), is not changed by preterm delivery, implying that plasticity is actually delayed relative to the birth date. A similar advance in the eye-specific segregation of retinal inputs was noted in the lateral geniculate nucleus. Previous reports had made the case that birth per se could cause changes in the physiology of neurons. For example, the physiological responses of neurons to GABA switch from excitatory to inhibitory at the time of delivery due to
the perinatal surge of maternal oxytocin (Tyzio et al., 2006). The study by Toda et al. takes this one step further by demonstrating that brain wiring can be modified by the timing of birth with a surprising advance, rather than a delay, in the maturation of the neuronal circuits. How could birth initiate the program that triggers barrel formation? One possibility is that sensory whisker stimulation could be at play. However, it had previously been shown, and was confirmed here, that sensory inputs are not required for barrel patterning (Erzurumlu and Gaspar 2012). Other potential candidates are changes in neurotransmitters that are involved in barrel development, such as glutamate or serotonin (5-HT). Examining potential changes in these transmitter systems, Toda et al. made the interesting observation that a drop in the extracellular levels of 5-HT occurs at birth. Using a combination of pharmacological methods to modulate 5-HT brain levels at birth, their experiments suggest that this reduction could be the initiating factor for barrel development, via a downregulation of 5-HT1B receptor stimulation on thalamocortical and retinal axons. This interpretation fits well with previous observations showing that stimulation of the presynaptic 5-HT1B receptor exerts a brake on barrel cortex and retinal map maturation, leading to interference with axon guidance molecules and presynaptic neurotransmission (reviewed in van Kleef et al., 2012). This is also consistent with the observation that in nutritionally restricted rats, an increase in brain levels of 5-HT and of 5-HT transporter expression was correlated with a delay in the formation of cortical barrels (Medina-Aguirre et al.,
Developmental Cell 27, October 14, 2013 ª2013 Elsevier Inc. 3
Developmental Cell
Previews 2008). A causal role for the decrease of 5-HT in barrel emergence is supported by experiments in which Toda et al. reduced 5-HT transmission with a pharmacological compound, PCPA, accelerating barrel emergence by one day. Although these experiments may appear difficult to reconcile with previous observations of normal or delayed maturation of the barrel cortex after pharmacologic or genetic depletion of serotonin (reviewed in van Kleef et al., 2012), one possible explanation for this discrepancy is that in the case of more drastic 5-HT depletion, such as that seen in genetic models, severe growth retardation leads to delayed cortical maturation of the upper cortical layers (Narboux-Neˆme et al., 2013). This delayed cortical maturation may then prevent the permissive effects on barrel formation observed by Toda et al. (2013) after milder and more local 5-HT manipulation. An important question raised by the present observations is that of the mechanisms triggering the reduction of 5-HT at birth. Transient serotonin transporter expression in several nonserotonergic brain structures is known to peak at birth, in particular in the ventrobasal thalamus
(reviewed in van Kleef et al., 2012), and this could contribute to the reduction of extracellular 5-HT brain levels. This clearly poses the questions of whether other changes in gene expression may be controlled by the timing of birth and whether these changes are triggered by hormonal or environmental factors. Another important question is how such results could translate to other species, in particular those with longer gestational times, such as humans. Mammalian species differ considerably in gestational length. Previous comparative analyses of somatosensory barrel development in six species (hamster, mouse, rat, gerbil, rabbit, and guinea pig) with increasingly longer gestation periods have shown that whereas barrels emerge a few days after birth in hamsters, mice, and rats, they appear perinatally in rabbits and prenatally in guinea pigs (Rice et al., 1985). It will therefore be of interest to see whether delaying the time of delivery in altricial species can modify pattern emergence, and if so, in which direction. Finally, it will be of interest to determine whether this premature map emergence has any consequences on functionality in adult life.
4 Developmental Cell 27, October 14, 2013 ª2013 Elsevier Inc.
REFERENCES Erzurumlu, R.S., and Gaspar, P. (2012). Eur. J. Neurosci. 35, 1540–1553. Hoerder-Suabedissen, A., Paulsen, O., and Molna´r, Z. (2008). J. Comp. Neurol. 511, 415–420. Huberman, A.D., Feller, M.B., and Chapman, B. (2008). Annu. Rev. Neurosci. 31, 479–509. Medina-Aguirre, I., Gutie´rrez-Ospina, G., Herna´ndez-Rodrı´guez, J., Boyzo, A., and ManjarrezGutie´rrez, G. (2008). Int. J. Dev. Neurosci. 26, 225–231. Narboux-Neˆme, N., Angenard, G., Mosienko, V., Klempin, F., Pitychoutis, P.M., Deneris, E., Bader, M., Giros, B., Alenina, N., and Gaspar, P. (2013). ACS Chem. Neurosci. 4, 171–181. Rice, F.L., Gomez, C., Barstow, C., Burnet, A., and Sands, P. (1985). J. Comp. Neurol. 236, 477–495. Toda, T., Homma, D., Tokuoka, H., Hayakawa, I., Sugimoto, Y., Ichinose, H., and Kawasaki, H. (2013). Dev. Cell 27, this issue, 32–46. Tyzio, R., Cossart, R., Khalilov, I., Minlebaev, M., Hu¨bner, C.A., Represa, A., Ben-Ari, Y., and Khazipov, R. (2006). Science 314, 1788–1792. van Kleef, E.S., Gaspar, P., and Bonnin, A. (2012). Eur. J. Neurosci. 35, 1563–1572. Vongdokmai, R. (1980). J. Comp. Neurol. 191, 283–294.
Previews The Birth of the Barrels Patricia Gaspar1,2,* and Reha Erzurumlu3 1INSERM
UMR-S 839, Universite´ Pierre et Marie Curie, 75005 Paris, France du Fer a` Moulin, 17 rue du Fer a` Moulin, 75005 Paris, France 3Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.devcel.2013.09.028 2Institut
Refinement of sensory maps follows a highly reproducible tempo dictated largely by peripheral sensory receptors and neural activity. In this issue of Developmental Cell, Toda et al. (2013) add a new twist by showing that the timing of birth plays a decisive role in setting the clock for pattern emergence. It makes perfect sense that the time spent in utero has different effects on the brain as compared to development after birth, when the newborn animal needs to rapidly adapt to its new sensory environment. However, testing the specific role of birth in neuronal development is difficult. Procedures that cause premature delivery in mice, such as hormonal changes or Caesarean extraction of embryos, are likely to have nonspecific and difficult-to-control effects such as decreased body weight and modified maternal behavior. Furthermore, the precise recording of birth dates and of neuronal maturation events can be a hurdle. This latter issue, however, can be overcome by taking advantage of neuronal pathways with stereotyped development. The somatosensory pathway, which originates in the whiskers and terminates in cortical structures known as barrels, and the eye-specific organization of retinal inputs in the lateral geniculate nucleus (the primary sensory relay of visual inputs) are two such pathways that have precise and well-described sequences of maturation. Previous studies have indicated the presence of some variability in the date of emergence of barrel patterns in the rodent somatosensory cortex in relation to the nutritional status and body weight of pups, but generally these studies saw delayed maturation due to malnutrition (Vongdokmai, 1980; Medina-Aguirre et al., 2008) or lower body weight (Hoerder-Suabedissen et al., 2008). In this issue of Developmental Cell, Toda et al. (2013) add a new twist on the usual temporal sequence of sensory map refinement by the peripheral sensory receptors and neural activity (Erzurumlu and Gaspar, 2012; Huberman et al.,
2008) by showing that the timing of birth plays a decisive role in setting the clock for neural circuit connectivity and pattern emergence. The authors examined the effects of premature birth on barrel patterning by inducing preterm delivery in three different ways: administration of mifepristone, a progesterone antagonist that causes premature delivery; ovariectomy, which also causes premature delivery; and Caesarian extraction. Although each of these approaches can have its own pitfalls, great care was taken to introduce the appropriate controls for each experimental paradigm. Strikingly, all three experimental conditions led to a one-day advance in the emergence of barrel patterns in the somatosensory cortex relative to the date of conception. In other words, this study indicates that barrel patterns emerge at a fixed date after birth, regardless of whether the animals were born prematurely. This is quite remarkable because the timing for patterning in the lower relay stations such as the thalamus or brainstem trigeminal relays is unchanged, being set to the date of conception rather than the date of birth. Indeed, the critical period for lesion-induced plasticity, which is known to depend on these lower sensory relays (Erzurumlu and Gaspar 2012), is not changed by preterm delivery, implying that plasticity is actually delayed relative to the birth date. A similar advance in the eye-specific segregation of retinal inputs was noted in the lateral geniculate nucleus. Previous reports had made the case that birth per se could cause changes in the physiology of neurons. For example, the physiological responses of neurons to GABA switch from excitatory to inhibitory at the time of delivery due to
the perinatal surge of maternal oxytocin (Tyzio et al., 2006). The study by Toda et al. takes this one step further by demonstrating that brain wiring can be modified by the timing of birth with a surprising advance, rather than a delay, in the maturation of the neuronal circuits. How could birth initiate the program that triggers barrel formation? One possibility is that sensory whisker stimulation could be at play. However, it had previously been shown, and was confirmed here, that sensory inputs are not required for barrel patterning (Erzurumlu and Gaspar 2012). Other potential candidates are changes in neurotransmitters that are involved in barrel development, such as glutamate or serotonin (5-HT). Examining potential changes in these transmitter systems, Toda et al. made the interesting observation that a drop in the extracellular levels of 5-HT occurs at birth. Using a combination of pharmacological methods to modulate 5-HT brain levels at birth, their experiments suggest that this reduction could be the initiating factor for barrel development, via a downregulation of 5-HT1B receptor stimulation on thalamocortical and retinal axons. This interpretation fits well with previous observations showing that stimulation of the presynaptic 5-HT1B receptor exerts a brake on barrel cortex and retinal map maturation, leading to interference with axon guidance molecules and presynaptic neurotransmission (reviewed in van Kleef et al., 2012). This is also consistent with the observation that in nutritionally restricted rats, an increase in brain levels of 5-HT and of 5-HT transporter expression was correlated with a delay in the formation of cortical barrels (Medina-Aguirre et al.,
Developmental Cell 27, October 14, 2013 ª2013 Elsevier Inc. 3
Developmental Cell
Previews 2008). A causal role for the decrease of 5-HT in barrel emergence is supported by experiments in which Toda et al. reduced 5-HT transmission with a pharmacological compound, PCPA, accelerating barrel emergence by one day. Although these experiments may appear difficult to reconcile with previous observations of normal or delayed maturation of the barrel cortex after pharmacologic or genetic depletion of serotonin (reviewed in van Kleef et al., 2012), one possible explanation for this discrepancy is that in the case of more drastic 5-HT depletion, such as that seen in genetic models, severe growth retardation leads to delayed cortical maturation of the upper cortical layers (Narboux-Neˆme et al., 2013). This delayed cortical maturation may then prevent the permissive effects on barrel formation observed by Toda et al. (2013) after milder and more local 5-HT manipulation. An important question raised by the present observations is that of the mechanisms triggering the reduction of 5-HT at birth. Transient serotonin transporter expression in several nonserotonergic brain structures is known to peak at birth, in particular in the ventrobasal thalamus
(reviewed in van Kleef et al., 2012), and this could contribute to the reduction of extracellular 5-HT brain levels. This clearly poses the questions of whether other changes in gene expression may be controlled by the timing of birth and whether these changes are triggered by hormonal or environmental factors. Another important question is how such results could translate to other species, in particular those with longer gestational times, such as humans. Mammalian species differ considerably in gestational length. Previous comparative analyses of somatosensory barrel development in six species (hamster, mouse, rat, gerbil, rabbit, and guinea pig) with increasingly longer gestation periods have shown that whereas barrels emerge a few days after birth in hamsters, mice, and rats, they appear perinatally in rabbits and prenatally in guinea pigs (Rice et al., 1985). It will therefore be of interest to see whether delaying the time of delivery in altricial species can modify pattern emergence, and if so, in which direction. Finally, it will be of interest to determine whether this premature map emergence has any consequences on functionality in adult life.
4 Developmental Cell 27, October 14, 2013 ª2013 Elsevier Inc.
REFERENCES Erzurumlu, R.S., and Gaspar, P. (2012). Eur. J. Neurosci. 35, 1540–1553. Hoerder-Suabedissen, A., Paulsen, O., and Molna´r, Z. (2008). J. Comp. Neurol. 511, 415–420. Huberman, A.D., Feller, M.B., and Chapman, B. (2008). Annu. Rev. Neurosci. 31, 479–509. Medina-Aguirre, I., Gutie´rrez-Ospina, G., Herna´ndez-Rodrı´guez, J., Boyzo, A., and ManjarrezGutie´rrez, G. (2008). Int. J. Dev. Neurosci. 26, 225–231. Narboux-Neˆme, N., Angenard, G., Mosienko, V., Klempin, F., Pitychoutis, P.M., Deneris, E., Bader, M., Giros, B., Alenina, N., and Gaspar, P. (2013). ACS Chem. Neurosci. 4, 171–181. Rice, F.L., Gomez, C., Barstow, C., Burnet, A., and Sands, P. (1985). J. Comp. Neurol. 236, 477–495. Toda, T., Homma, D., Tokuoka, H., Hayakawa, I., Sugimoto, Y., Ichinose, H., and Kawasaki, H. (2013). Dev. Cell 27, this issue, 32–46. Tyzio, R., Cossart, R., Khalilov, I., Minlebaev, M., Hu¨bner, C.A., Represa, A., Ben-Ari, Y., and Khazipov, R. (2006). Science 314, 1788–1792. van Kleef, E.S., Gaspar, P., and Bonnin, A. (2012). Eur. J. Neurosci. 35, 1563–1572. Vongdokmai, R. (1980). J. Comp. Neurol. 191, 283–294.