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1 Department of Biology, University of Washington, Seattle WA 98195-1800, USA
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(Received 29 April 2005;
accepted after revision 31 May 2005;
first published online 2 June 2005)
Corresponding author M. Bosma: Department of Biology, University of Washington, Seattle WA 98195-1800, USA. Email: martibee{at}u.washington.edu
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Introduction |
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In the chick hindbrain after the period of rhombomeric segmentation, spontaneous firing is synchronized between homologous motor roots on both sides of the hindbrain, and between different motor roots along the rostrocaudal axis (Fortin et al. 1995). Our previous experiments used retrograde dextran labelling to identify motor neurones of embryonic mouse hindbrain cranial nerve nuclei and demonstrated that motor neurones develop spontaneous synchronous [Ca2+]i transients at E11.5 (Gust et al. 2003), a time that coincides with the loss of boundaries between rhombomeres (r) 1–7. We observed tight synchronization between motor neurones that were not in close proximity as well as between identified motor neurones and nearby non-labelled neurones. These data imply that a widely distributed mechanism of coordination exists within the hindbrain (Fortin et al. 1995), but such a pacemaker region had not been identified.
We demonstrate here that spontaneous synchronized activity at E11.5 in the mouse hindbrain includes large regions of the hindbrain, beyond motor neurone pools. In addition, our results suggest that midline serotonergic neurones participate in driving that activity. Activity propagates from the midline neurones to lateral regions, physical separation of midline neurones from the lateral hindbrain disrupts lateral activity, 5-HT2A receptor antagonists block activity in all regions, and immunoreactive 5-HT2A receptors are present throughout the hindbrain.
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Methods |
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Counting of neuronal cells to identify the proportion of serotonergic neurones was performed by examining the rostral–caudal extent of the hindbrain where serotonergic neurones are observed (approximately 680 µm, see Fig. 4B). This area was sampled by taking every third slice in a rostral–caudal sequence and counting cell profiles in the central optical plane (3 µm thick) only. Any DAPI profile less than one half-diameter of the average of the neurones around it was not included in the cell counts. As neurones become postmitotic and exit the cell cycle, they move towards the pial side of the ventricular zone and begin to express neuronal characteristics such as TuJ1 and serotonin, but often have processes that trail towards the ventricular zone. These neurones that were newly postmitotic were included in the neuronal counts. The most rostral section of the serotonergic neurone nucleus was not included in the total neurone count. However, even at that rostral border, 59% of the TuJ1-positive neurones (n = 114 neurones) were immunopositive for serotonin.
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Results |
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Such widespread spontaneous activity might be generated as an emergent property of the neural circuitry at these stages, or might be driven by a discrete pacemaker region. In the above experiments, we observed that some transients (27 ± 6%, n = 19 experiments) occurred only near the midline and were not recorded laterally; isolated lateral transients were never observed. Several examples of midline-only transients are marked with open circles in Figs 1A, 2A and 3A.
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To measure the direction and speed of propagation of [Ca2+]i transients we used an array of 9–12 equally spaced small recording sites, beginning approximately 25 µm from the anatomical midline (within the bright band of fluo-4-loaded cells) and spanning between 600 and 700 µm of the mediolateral axis. Using this recording array, activity was observed that propagated from the midline towards more lateral regions at a rate of 241 ± 18 µm s–1 (Fig. 2, n = 11 measurements in 8 preparations). Propagation of widespread events from lateral to medial regions was not observed.
If midline activity initiates activity in lateral regions, physical separation of lateral and medial regions should inhibit lateral activity, or desynchronize it from the midline. To test this, activity was imaged in the intact hindbrain; medial and lateral regions were then completely cut apart and the tissue re-imaged as two separate portions (Fig. 3). In 16/18 experiments, the activity of transients in lateral tissue stopped entirely (n = 6) or the frequency decreased (n = 10; from 2.1 ± 0.4 to 0.7 ± 0.2 events min–1, P < 0.001) after separation. In the remaining two experiments, the initial lateral activity was relatively slow (0.4 and 0.38 events min–1), and the activity after separation from the midline increased in each case to 0.6 events min–1. In contrast, the frequency of activity in midline tissue was not affected (from 3.0 ± 0.3 to 2.6 ± 0.3 events min–1, P = 0.3, n = 18) (Fig. 3D). When activity remained in isolated lateral regions, it was no longer synchronous with that in medial tissue (compare Fig. 3A and B).
These experiments suggest that in intact hindbrain, medial cells in a region within approximately 125 µm of the midline serve as drivers for overall activity in both medial and lateral regions. This also demonstrates that lateral tissue, in some preparations, is able to generate spontaneous activity at a frequency that is overridden in intact hindbrain by the midline driver.
The serotonergic raphe neurones are among the most prominent midline neurones in the embryonic hindbrain. This system develops as two groups of neurones within the hindbrain – a rostral group that begins to express serotonin at E11.25–11.5 in mouse, and a caudal group that expresses serotonin one day later (Hendricks et al. 2003). To determine whether these serotonergic neurones are located at the same points that defined our midline neurones in the above imaging experiments, we performed immunocytochemistry for serotonin (Fig. 4). In a sagittal section taken approximately 20 µm lateral to the midline, serotonin-immunoreactive somata are observed; in addition, immunopositive axons can be seen extending both rostrally into the midbrain and caudally towards the spinal cord (Fig. 4A). In a section taken approximately 60 µm lateral to the midline in the sagittal plane, a larger group of serotonin-immunoreactive somata are observed; this indicates that the somata are located at least within 20 µm of the midline, and extend laterally at least 60–80 µm. In the anterior–posterior axis, serotonin-immunopositive somata are aggregated in a group beginning 150 µm caudal of the isthmus and extending approximately 680 µm caudally into the hindbrain (Fig. 4B). When examined in horizontal sections (Fig. 4C), serotonin-immunoreactive neurones are located immediately ventral to the ventricular zone, in a group ending approximately 150 µm from the midline (the non-neuronal cells of the floor plate are medial to the serotonergic cell bodies). These neurones have extensive processes in the axon-dense marginal zone, including some that cross the midline (Fig. 4C). Thus the serotonergic neurones are in the same region as the band of fluo-4 loaded cell bodies that defined the midline region in the imaging experiments above, and within which spontaneous activity appears to originate.
In order for these serotonergic midline neurones to play a role in initiation of spontaneous activity, 5-HT receptors must be present in the hindbrain at this stage. To determine this, we performed immunocytochemistry for the 5-HT2A receptor. Figure 5B, a horizontal cryosection from an E11.5 b1-dextran-injected animal, demonstrates localization of the 5-HT2A receptor. The receptor is expressed in decussating axons at the midline and in the entire marginal zone of the hindbrain, from medially near the serotonergic neurone region, laterally past the exit points of the branchiomeric motor axons. Label is reduced in the region of the trigeminal motor nucleus (nV), where the dextran-identified motor neurones fluorescing at 594 nm (red) are shown. Expression of the 5-HT2A receptor is also seen on the motor axons exiting the hindbrain, and the sensory axons of the trigeminal sensory ganglion (gV) outside of the hindbrain.
Localization of the 5-HT2A receptor was compared to the position of serotonergic neurones in the midline region in tissue on which dual immunocytochemistry was performed (Fig. 5C). Receptor expression is high in the axons crossing the ventral midline commissure. Receptor expression is also high in a few serotonin-immunoreactive neurones (arrowheads). Outside of the high expression in the serotonin neurone area and in the medio-lateral extent of the marginal zone, 5-HT2A receptor expression is punctate in the cell body layer (future grey matter), and does not extend into the ventricular zone.
If serotonergic neurones of the midline contribute to initiating widespread spontaneous activity, serotonin receptor antagonists should block activity or modulate lateral spread. Ketanserin (an antagonist at the 5-HT2A receptor; Barnes & Sharp, 1999) had no effect on spontaneous activity at a concentration of 1 µM (Fig. 6A, n = 3); at 5 µM, the activity slowed to 76 ± 3% of control (6/7 experiments), or was abolished (1/7 experiments). When 10 µM ketanserin was applied, it either slowed the activity (to 43 ± 1% of control, 4/26 cases) or abolished activity completely (22/26 cases) in a reversible manner (Fig. 6B). In three cases, there was a slight facilitation of the response to 10 µM ketanserin (increase in frequency to 108%); no facilitation was seen at lower doses. Application of spiperone, another 5-HT2A receptor blocker, had no effect at 10 nM (Fig. 6C, n = 3), but at 20 nM completely and reversibly blocked the activity (Fig. 6D, n = 6). Although activity did return with drug washoff, it was small compared to the control condition. This is in part due to the fact that the amplitude of [Ca2+]i transients tended to diminish over the course of these long experiments (see Fig. 6A and C). However, recovery included synchronous transients between regions, indicating that block of the 5-HT2A receptor did not de-synchronize events between cells, but appeared to block the initiation of synchronized spontaneous activity. Methiothepin, a 5-HT1B/1D/2C/7 antagonist, at 100 µM, did not block activity (n = 4). With prolonged application of ketanserin (45–60 min), activity remained blocked, suggesting that other transmitters do not assume the role of initiating synchronization in the hindbrain. This is unlike the situation in spinal cord, where multiple transmitters involved in network synchronization are able to re-initiate activity when one transmitter is blocked (O'Donovan, 1999). Blockade of receptors for glutamate (CNQX – 25 µM, MK801 – 20 µM), glycine (strychnine –5 µM), GABA (bicuculline – 50 µM, picrotoxin – 10 µM), ACh (d-tubocurarine – 10 µM), or noradrenaline (yohimbine – 25–50 nM, prazosin – 25–50 nM) alone or in combination, did not block activity (data not shown). These data demonstrate that serotonin is unique in its ability to mediate spontaneous activity, and further implicates the midline serotonergic neurones as the primary initiators of that activity.
Serotonin, either alone or after inhibition of the serotonin transporter with citalopram (5 nM, n = 8), at concentrations of 1.0 µM (n = 2) or at 10–50 µM (n = 16) did not modulate the activity. DOI (a 5-HT2A receptor specific agonist) at a concentration of 5 µM increased the frequency of activity in 1/7 experiments; there was no effect in the remaining experiments. At 20–50 µM, DOI elicited an increase in midline or lateral activity in approximately half (10/23) of the preparations (1.9 ± 0.2-fold increase, n = 8; DOI also initiated activity in two quiescent preparations), while having no effect in 13/23 preparations; however, these effects were not significant when the entire sample was considered. The variability of the DOI response and the lack of any significant effect of serotonin could occur because the receptor desensitizes rapidly to the bath-applied agonist or the endogenous serotonin can fully activate the receptors involved the initiation of spontaneous synchronous activity.
Because the serotonergic neurones are not the only cells in the midline regions, it remains possible that the non-neuronal ventricular zone cells or non-serotonergic neurones present in our midline regions participate in some way in the activity. To investigate this possibility, we assayed the fraction of total neurones in our defined midline region that the serotonergic cells represent, and determined directly the participation of non-neuronal ventricular zone cells in spontaneous activity.
To determine the fraction of midline neurones that are serotonergic, cryosections were immunoreacted against both serotonin and the neuronal marker TuJ1, and sections were then counterstained with DAPI to show nuclei within the hindbrain slices (Fig. 7). Cells within 125 µm of the midline were then counted, and TuJ1-expressing neurones classified by whether they expressed serotonin. The ventricular zone was identified as a continuous array of relatively elongated nuclei, with no TuJ1 staining. In our sample of sections (n = 789 neurones in 11 sampled regions), 82 ± 7% of all TuJ1-positive neurones within 125 µm of the midline were serotonin-positive. This count includes newly differentiated neurones with ventricular zone processes. Thus, the majority of neurones within the region where spontaneous activity initiates in the hindbrain are serotonergic.
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Discussion |
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Regions that initiate or drive activity have not been clearly demonstrated in other areas of the developing brain where synchronized spontaneous activity is observed. In developing chick spinal cord, the higher excitability of motor neurones is postulated to activate Renshaw-like interneurones, which then synchronize activity throughout the spinal cord by enhancing network excitation (Wenner & O'Donovan, 2001). In the developing hippocampus, either septal or hilar neurones have been postulated to drive synchronous activity (Strata et al. 1997; Leinekugel, 1998). Neither region, however, appears to be capable of independent activity when isolated.
In the developing rat hippocampus, spontaneous activity takes the form of giant depolarizing potentials (GDPs) or early network oscillations (ENOs), driven primarily by GABA excitation during the stages when the Cl– equilibrium potential is relatively positive (Ben-Ari et al. 1989; Garaschuk et al. 1998; Ben-Ari, 2002). Widespread synchronous activity in the developing cortex has been shown by [Ca2+]i imaging (Garaschuk et al. 2000; Corlew et al. 2004). This activity is not blocked by antagonists of the GABAA receptor although GABA is excitatory, but is sensitive to pharmacological blockade of both NMDA and non-NMDA receptors (Leinekugel et al. 1997). In contrast to neonatal cortical slices, neonatal cortical neurones in dispersed cultures generate synchronous activity that appears to emanate from a population of GABAergic subplate neurones (Voigt et al. 2001). Spontaneous activity in the chick spinal cord is driven by redundant glutamatergic, nicotinic and GABAergic/glycinergic systems, acting in a network system of mutual excitation to drive synchronicity (Chub & O'Donovan, 1998; O'Donovan, 1999; Tabak et al. 2001). Although the network changes the dependence on these transmitters over developmental time, they may substitute for each other under experimental conditions. In mouse spinal cord, motor neurones acting via nicotinic receptors and GABAergic interneurones can generate local episodes of spontaneous activity, while the ability to spread that activity between segments requires glycinergic components (Hanson & Landmesser, 2003). The serotonergic dependence of spontaneous activity in these developing brain regions has not been tested. The hindbrain may be unique in utilizing serotonin to initiate and propagate spontaneous activity, perhaps due to the fact that the raphe system is developing within it. A dependence on serotonin of the late fetal respiratory rhythm has been demonstrated in rats (Di Pasquale et al. 1994).
We have shown that spontaneous synchronized activity initiates in a relatively narrow region around the rostral midline of the hindbrain, in the exact position where a large population of serotonergic neurones are differentiating. We have demonstrated that over 80% of the neurones at the midline are serotonergic; the identity of the remaining neurones is not known. In order to ascertain whether the fluo-4-loaded midline neurones that are in the region of activity initiation are serotonergic, we attempted to immunolabel the fluo-4-loaded neurones using the fixative 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), which has been shown to fix calcium indicators and chelators in cells (Tymianski et al. 1997). However, whether we used 3% EDC in ACSF (n = 7), or a combination of 4% PFA–1% EDC in ACSF (n = 3) or 4% PFA–3% EDC in ACSF (n = 2), the fluo-4 signal was not observed, and the immunoreactivity for serotonin was degraded. These experiments do not clarify whether the active, fluo-4-loaded neurones were actually the serotonergic neurones that initiate activity. However, the overlay of the fluo-4-loaded neurones with the serotonin immunoreactivity in the same slice, shown in Fig. 8B, demonstrates that the region where activity initiates in these [Ca2+]i imaging experiments is indeed serotonergic. It is possible that serotonin released tonically from midline neurones is acting in a permissive manner to allow other midline neuronal cells to generate activity; however, given that less than 20% of the midline neurones are not serotonergic-immunopositive and that non-neuronal cells are not active, this is an unlikely scenario. Thus, whether serotonergic neurones are acting as independently active pacemakers or in a mutually excitatory network that includes a relatively small proportion of other neurones, it is highly probable that they are the major initiators of the activity that is then propagated through the hindbrain.
It is possible that a proportion of midline neurones are serotonin-immunopositive due to the uptake of surrounding transmitter rather than by biosynthesis. This is unlikely, since in rat, the expression of the ETS domain transcription factor PET-1, a specific marker for serotonergic neurones, is restricted to neurones that coexpress the synthetic enzymes for serotonin and the serotonin transporter (Hendricks et al. 1999); thus the neurones expressing the transporter are themselves serotonergic. In mouse, the serotonin transporter is expressed in rostral hindbrain very closely opposed to the midline (Bruning et al. 1997). Even if some proportion of neurones do not synthesize serotonin, they are probably involved in signalling by serotonin, and are likely to play a role in the generation of spontaneous activity.
Spontaneous activity in the developing cortex has been shown to be initiated and propagated in the ventricular zone by radial glial cells (Weissman et al. 2004). We demonstrate here that the activity that we observe is neither generated nor propagated in the ventricular zone of the hindbrain. Radial glial cells, identified by RC2 immunoreactivity, are relatively sparse in the hindbrain at this point of development (data not shown), and we have not observed propagation of a signal from the ventricular zone towards the pial surface or vice versa in slice experiments. The serotonergic neurones are the most medial differentiated group of neurones in the hindbrain. Medially positioned branchiomeric motor neurones differentiate relatively early, but migrate laterally, while non-branchiomeric motor neurones (cranial nerves IV and VI) are not found at the same rostro-caudal position in the hindbrain as the serotonergic neurones at E11.5.
Because some of the isolated lateral regions of the hindbrain are able to maintain a slow rhythm in the presumed absence of midline serotonergic inputs, it is possible that hindbrain neuronal populations participate in excitatory network interactions that prime the tissue for spontaneous activity. Our experiments suggest that the midline serotonergic neurones provide the additional excitatory inputs that then initiate widespread activity. Application of the serotonergic agonist DOI did not consistently activate or increase activity in isolated lateral regions: in one experiment, DOI (50 µM) caused one transient in quiescent lateral tissue; an average increase in frequency of 1.66 (to an average rate of 1.45 events min–1, n = 2, 20 µM DOI) in two experiments; and no effect in another (20 µM). However, these frequencies are not similar to those of midline regions or of lateral regions before the surgical separation. These experiments may be difficult to interpret, since the network properties of the cut tissue may be modified by the surgery.
The serotonergic system is broadly distributed throughout the central nervous system, and numerous behaviour disorders are attributed to serotonin deficiencies that may be associated with developmental abnormalities (Whitaker-Azmitia, 2001). Excess serotonin is implicated in autism-related disease, whereas deficits in serotonin predispose to mood disorders (Chugani et al. 1999; Betancur et al. 2002; Gross et al. 2002). The serotonergic system is also implicated in development of the cortex (Luo et al. 2003; Vitalis & Parnavelas, 2003), and neuronal differentiation (Lauder et al. 2000). In addition, neurones of the dorsal raphe, which innervate the frontal cortex widely, are rhythmically active during waking states, indicating a role for these neurones in general arousal of the CNS (Jacobs & Fornal, 1991). Spontaneous activity may be a feature of serotonergic neurones at all points in their maturation: this activity may be important in formation of physiological circuits within the developing CNS as well as having an important neuromodulatory function in the adult CNS.
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