The brain of a developing fetus has a big job to do: it needs to create the important connections between neurons that the individual will need later in life. This is a challenge because the first connections that form between neurons are sparse, weak and unreliable. They would not be expected to be able to transmit signals in a robust or effective way, and yet they do. How the nervous system solves this problem is an important question, because many neurological disorders may be the result of bad wiring between neurons in the fetal brain.

When an adult human or other mammal “sees” an object, visual information from the eye is transmitted to a part of the brain called the thalamus. From there it is sent on to another part of the brain called the cortex. The cortex also provides feedback to the thalamus to adjust the system and often acts as a brake in adults to limit the flow of information from the eyes.

Murata and Colonnese investigated whether the fetal brain contains any “booster” circuits of neurons that can amplify weak signals from other neurons to help ensure that information is transferred accurately. The experiments monitored and altered visual activity in the brains of newborn rats – which have similar activity patterns to those observed in human babies born prematurely. Murata and Colonnese found that in these rats the feedback signals from the cortex to the thalamus actually multiply the visual signals from the eye, instead of restraining them. This causes a massive amplification in activity in the developing brain and explains how the fetal brain stays active despite its neurons being only weakly connected.

The booster circuit stops working just before the eyes first open (equivalent to birth in humans) as the connections between neurons become stronger, and is replaced by the braking mechanism seen in adults. This is important, because continued amplification of signals in the adult brain might cause excessive brain activity and epilepsy. The findings of Murata and Colonnese may therefore help to explain why epileptic seizures have different causes and behave differently in children and adults.

The next step following on from this work is to find out how the braking mechanism forms in young animals. Future studies will also focus on understanding the precise role the booster circuit plays in early brain development.

Throughout the central nervous system, before the development of sensory input or behavioral experience, specialized circuitry generates spontaneous activity that is required for circuit formation (Kirkby et al., 2013). In sensory isocortex the vast majority of spontaneous activity is not generated locally, but rather in the peripheral sense organ (Khazipov et al., 2013a). For example, prior to vision the retina generates waves of spontaneous firing that refine receptive field characteristics in visual thalamus and cortex (Huberman et al., 2008). Retinal waves drive robust firing in LGN, superior colliculus, and VC (Ackman and Crair, 2014) through a complex interaction between these structures (Weliky and Katz, 1999) that remains poorly understood. In the retina, transient circuit properties are responsible for wave propagation, most prominently hyper-connectivity of starburst amacrine cells (Blankenship and Feller, 2010), but the degree to which the central transmission of retinal waves, or spontaneous activity in other systems, requires similar specializations is unknown.

During the period of retinal waves, early ganglion cell activity undergoes both amplification and transformation in the brain in ways substantially different from the adult transmission of retinal activity, suggesting the presence of unique developmental circuitry. For example, the relative amplification of ganglion cell spiking in developing thalamocortical circuits is approximately 40-fold that of the adult (Colonnese et al., 2010). Evidence of similar amplification is observed in late second and early third trimester human neonates (born preterm), who show sensory-evoked and spontaneous EEG events that are paradoxically large, reaching amplitudes of over 1 millivolt, compared to microvolts in adults (Vanhatalo and Kaila, 2006). These strong neonatal activities persist despite low synaptic density (5–10% of the adult) (Aggelopoulos et al., 1989; Bourgeois and Rakic, 1993), weak individual synapses (Chen and Regehr, 2000; Etherington and Williams, 2011), and poor action-potential reliability (McCormick and Prince, 1987). Not only is retinal wave activity amplified in the thalamocortical pathway, it is also transformed into synchronized rapid oscillations that enhance propagation and synaptic plasticity (Khazipov et al., 2013b; Luhmann et al., 2016). Cortical activity during the period of retinal waves follows nearly exactly the macro-patterning of retinal activity: periods of silence lasting 30–60 s are interrupted by 500 ms–2 s waves that occur in clusters lasting up to 10 s (Hanganu et al., 2006; Colonnese and Khazipov, 2010; Ackman et al., 2012). However, the cortical activity within waves is organized in rapid ‘spindle-burst’ oscillations (8–30 Hz) (Hanganu et al., 2006; Kummer et al., 2016) that are not present in retina and not observed in adult cortical activity, suggesting transitory early circuit properties are responsible for their production (Tolner et al., 2012). Spindle-bursts are not limited to VC, but are ubiquitous throughout neonatal cortex. They are the rodent homologue of delta-brushes (Khazipov et al., 2013a), one of the major components of the human preterm EEG (André et al., 2010), and their absence in patients indicates a poor prognosis. Thus understanding their central generative mechanisms would be a critical contribution to neonatal health and development.

We hypothesized that spindle-burst oscillations and retinal-wave amplification arise in LGN, but depend critically on corticothalamic feedback (Weliky and Katz, 1999). To test this we recorded simultaneously from LGN and primary VC of head-fixed, unanesthetized rats both during the period of retinal waves (P5-11), and immediately after (P13-14), when mature cortical activity patterns have begun to emerge (Rochefort et al., 2009; Colonnese, 2014; Hoy and Niell, 2015). We investigated the relative roles of retina, thalamus and cortex by pharmacological or optogenetic modulation of each region. Our results demonstrate a developmentally unique role for the corticothalamic projection that results from the late development of inhibition relative to excitation, and is necessary for the propagation and synchronization of retinal wave-driven activity through thalamus and cortex.

To determine the thalamic contribution to the generation of spindle-burst oscillations evoked by spontaneous retinal waves, we made simultaneous recordings from the LGN and monocular VC in head-fixed, unanesthetized rats. We focused on post-natal days (P) 9–11, the time of peak stage-III (glutamatergic) retinal wave activity when cortical activity is dominated by 20–30 Hz spindle oscillations that synchronize all layers (Colonnese and Khazipov, 2010). Linear multi-electrode arrays were used to acquire local field potential (LFP) and multi-unit spike activity (MUA) through the depth of LGN and VC (Figure 1A,B). Whole-field visual stimulation was used to identify L4 in VC and eye-specific lamina in LGN. The LGN channel with maximal contralateral visual response was used for analysis. The VC and LGN recordings were not topographically aligned. This allows investigation of the oscillations in each structure reported here, but not precise phase relationships between LGN and VC during spontaneous activity.

Figure 1

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As previously described (Colonnese and Khazipov, 2010), spontaneous activity in VC during the retinal wave period consisted of long periods of network silence interrupted by periods of activity lasting 3–10 s. Activity within these active periods consisted of spindle-shaped oscillations in the local field potential (LFP) in superficial layers with a primary frequency of 20.8 ± 0.8 Hz (n = 7, mean ± SEM) and elevated MUA in all layers (Figure 1D,H). Activity in LGN had a similar structure: 5–10 s periods of spiking activity alternating with periods of low or absent spiking (Figure 1C). Because the amplitude of the LGN LFP was lower than the median spike amplitude, it was not analyzed further. To determine if the spindle-burst oscillations observed in VC originate in LGN, we quantified the frequency modulation of LGN MUA. Spike-rate modulation in LGN showed a primary frequency of 23.1 ± 0.6 Hz (n = 7) (Figure 1G), similar to VC. Thus, spindle-burst oscillations are also observed in LGN. Combined with the absence of significant oscillatory ganglion cell firing during waves (Colonnese and Khazipov, 2010), and the location of the VC spindle-bursts’ current sink in the input layer, this data supports a thalamic origin of spindle-burst oscillations.

Spindle-burst oscillations require retina and thalamus

To quantify the contribution of retinal input to spontaneous activity in LGN (Figure 2A) and VC (Figure 2B), we acutely silenced both eyes by intraocular injection of the blood brain barrier-impermeant glutamate receptor antagonists APV and CNQX. Silencing was confirmed by loss of the visual response (not shown). As predicted, retinal silencing dramatically reduced firing rates in LGN (–86.6 ± 3.9%, mean ± SEM) and VC (–67.2 ± 10.2%). The continuity of activity, measured as the proportion of the recording with spike activity (periods containing at least two spikes with an interval of less than 500 ms, called 'events'), was also significantly reduced (LGN –88.5 ± 6.5%, VC –90.6 ± 2.3%). Examination of the distribution of event lengths after retinal silencing showed that events over 5 s in duration were reduced in LGN and eliminated in VC (Figure 2A4,B4). Retinal silencing largely eliminated the prominent peak in LGN MUA and VC LFP spectra in the spindle-burst range, leaving only lower frequency activity (Figure 2A5,B5). In combination with previous results showing that spindle-burst oscillations are driven by retinal waves (Colonnese and Khazipov, 2010), the present retinal silencing data confirms that in LGN, as in VC, spontaneous retinal activity is the primary driver of spontaneous activity and spindle-burst oscillations. In the absence of retinal input, spontaneous activity in the intact thalamocortical loop can provide at most 20% of normal LGN firing.

Figure 2

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To determine the ability of VC alone to generate spontaneous activity and spindle-burst oscillations, we pharmacologically silenced LGN by local injection of the GABA receptor agonist muscimol (Figure 2C). Silencing LGN significantly reduced VC L4 MUA rate (–79.0 ± 3.9%) and continuity (–89.0 ± 2.6%) (Figure 2C3). The remaining VC activity consisted only of very short bursts (<1 s) (Figure 2C4). Most importantly, LGN silencing completely eliminated oscillatory activity in the VC LFP (Figure 2C5). All of these activity reductions were more severe than observed following retinal silencing; thus while VC alone can generate very short bursts of activity, as observed in slices (Allène et al., 2008), an intact thalamocortical loop is necessary for the generation of activity lasting longer than 1 s that contains any high frequencies. In total these data confirm and extend previous results in somatosensory (Minlebaev et al., 2011; Yang et al., 2013a) and visual (Colonnese and Khazipov, 2010) cortex that spindle-burst oscillations first emerge in thalamus in response to retinal or sensory input.

Transmission of retinal waves requires corticothalamic feedback

The thalamic and cortical activity remaining after retinal and LGN silencing suggests that corticothalamic excitation is at least partially functional in neonatal rats, as has been previously demonstrated in ferrets (Weliky and Katz, 1999). We therefore tested the hypothesis that VC provides critical amplification and transformation of the retinal input in LGN by silencing VC with local application of APV and CNQX (Figure 3). Silencing VC at P9-11 during the peak of stage III waves reduces LGN spike-rate by 79.2 ± 5.6% and continuity by 68.4 ± 9.3% (Figure 3D2). Remarkably, these activity reductions are of similar magnitude to those caused by retinal silencing. The fact that silencing of either retina or VC results in a greater than 50% reduction in firing indicates that they act synergistically to drive LGN. One explanation is that VC participates in feedback amplification as part of an excitatory loop with LGN that is necessary for the generation of effective thalamic spiking during retinal waves. The effect of VC silencing was limited to the LGN; spike-rates for all contacts from the same shank located 20–100 µm below the last visually responsive contact were not affected (+3.1 ± 17.1%, p=1.000, n = 6, Wilcoxon signed rank test), indicating that the pharmacological silencing of VC did not have systemic effects. Event duration was reduced, but not as severely altered as by retinal silencing (Figure 3D5), indicating that retina initiates and maintains activity in LGN, but VC prolongs it. Silencing VC strongly reduced normalized spike spectral power in the spindle-burst range (Figure 3D3). VC input appears to be required for normal patterning of the spindle-oscillations, as peak frequency of remaining activity shifted from 24.6 ± 0.9 to 16.2 ± 2.0 Hz (Figure 3D4) after VC silencing. These results show that during the period of peak stage III retinal waves, feedback connections from VC to LGN are a critical component of retinal wave transmission, which serve to both amplify and prolong spontaneous activity as well as accelerate spindle-burst oscillations in LGN.

Figure 3

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Retinothalamic innervation precedes cortical innervation of the thalamus (Seabrook et al., 2013). To determine whether corticothalamic feedback is also critical for the stage II retinal waves (cholinergic) present during the first post-natal week, we examined the effect of VC silencing at P5-7 (Figure 3C). Spindle-burst oscillations are slower at this age, resulting in a peak frequency of the L4 LFP spectra of 12.2 ± 1.7 Hz (data not shown). Spontaneous LGN spike-rate frequency is similarly down-shifted (16.0 ± 1.2 Hz). Silencing VC at this age significantly reduced spike-rates (−52.0 ± 7.4%) and continuity (−49.8 ± 10.7%) (Figure 3C2), showing that corticothalamic amplification is present at this age as well. However, there was no significant effect of VC silencing on either spike spectra or event duration (Figure 3C3–5). Thus during the first post-natal week, the role of VC is limited to amplification. At this age, LGN is able to generate spindle-oscillations in response to retinal waves, albeit with a lower frequency than during the second postnatal week. The difference between P5-7 and P9-11 demonstrates a shift in the role of corticothalamic feedback from simple amplifier to active participant in the shaping of LGN oscillations.

Spontaneous activity in VC dramatically changes between P11 and P13. Cortex no longer exhibits the long silent periods of immaturity; activity becomes continuous and loses the prominent spindle-oscillations, which are replaced by adult-like, broad-band activity (Colonnese and Khazipov, 2010). To determine if the LGN requirement for corticothalamic feedback is restricted to the period of retinal waves, and what role VC plays in the maturation of spontaneous activity, we silenced VC while recording from LGN at P13-14. VC silencing at this age does not decrease LGN activity, but rather increases spike rates (+26.2 ± 5.4%) and there is slight but not significant increase in continuity (+13.5 ± 5.0%) (Figure 3E2). VC silencing increases the proportion of very long duration events (>10 s) (Figure 3E5), but does not change the LGN MUA spectrum (Figure 3E3). Thus the excitatory role of corticothalamic feedback is limited to the period of retinal waves, and cortex becomes inhibitory to thalamus around eye-opening.

Together the VC silencing experiments indicate a continually changing role for corticothalamic feedback in the transmission of retinal activity during development. During the period of retinal waves, VC essentially gates LGN output, first as a simple amplifier of LGN, and later in the second post-natal week, by amplifying and patterning oscillations in LGN. This amplification role ends before eye-opening, after which corticothalamic feedback plays a less prominent role in the generation and patterning of retinal transmission through thalamus.

Absence of inhibition facilitates corticothalamic feedback excitation

To determine the mechanism of early corticothalamic feedback excitation and rhythmogenesis, we took advantage of the fast kinetics and high sensitivity of the blue light drivable channelrhodopsin Chronos (Klapoetke et al., 2014) to gain control of VC neurons within a few days of birth. Injection of AAV-Chronos-GFP into VC at P0-1 yielded strong expression in VC neurons in all layers and axon terminals by P6. In neonatal mice (Seabrook et al., 2013; Grant et al., 2016) cortical axons avoid LGN relative to surrounding thalamic nuclei. We observed the same pattern in VC axons expressing Chronos-GFP (Figure 4B), although cortical axon arbors can be seen within LGN even at P6. A 10 ms pulse of 470 nm LED on VC was sufficient to activate deep VC layers at all ages with similar delay (P6-7 3.7 ± 1.8 ms; P9-11 3.4 ± 1.5 ms; P13-14 3.5 ± 1.3 ms). At all ages, 10 ms light-pulses onto VC evoked short duration (~30 ms) initial spiking in LGN (Figure 4C,D), although the latency to activate LGN following VC activation decreased between P6-7 (34.2 ± 2.7 ms) and P9-11 (21.5 ± 0.5 ms), stabilizing by P13-14 (20.0 ± 0.9 ms) (Figure 4E). The probability of generating a spiking response in LGN with each VC activation increased from 39.7 ± 7.0% at P6-7 to 92.4 ± 3.6% at P13-14 (Figure 4F). The spike rate increase was similar in all three ages (Figure 4G).

Figure 4

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The major developmental change in the LGN response occurred between P9-11 and P13-14. It consisted of the development of post-stimulus inhibition following the initial evoked response (Figure 4H). The relative increase in LGN spike-rates at 100–250 ms after VC stimulation switched from neutral or positive (P6-7 −0.1 ± 36.7%; P9-11 +63.4 ± 61.0%) to negative at P13-14 (−89.2 ± 8.8%) indicating the recruitment of functional feedforward inhibition into the corticothalamic circuit between P11 and P13.

To determine how the increasing speed, reliability and inhibition of corticothalamic feedback could contribute to the ability of VC to generate spindle-burst oscillations at P9-11, but not P5-7 or P13-14, we examined the LGN response to patterned VC stimulation at these ages. Five 10 ms light pulses at 20 Hz evoked different responses in LGN at each age (Figure 4I). At P6-7, 20 Hz VC stimulation increased LGN spike rates but did not induce oscillatory activity. In contrast, the same stimulation at P9-11 induced 20 Hz oscillatory firing in LGN. At P13-14, despite reliable LGN responses to the first one or two pulses, induced inhibition prevented further oscillation.

Together these cortical stimulation experiments provide a mechanistic explanation for the changing role of corticothalamic feedback in shaping LGN activity. During cholinergic retinal waves, connectivity is sufficient for VC to amplify retinal waves in LGN but its reliability and velocity are insufficient to synchronize LGN firing. Then during the second postnatal week when glutamatergic waves predominate (P9-11), increasing speed and reliability of the feedback loop enables cortex to synchronize LGN at higher frequencies than LGN alone would naturally oscillate. Finally, at the transition to the third week (after P13), VC afferents recruit an inhibitory circuit, which reduces their ability to synchronize activity at high frequencies and makes the net effect of corticothalamic feedback inhibitory, as in the adult.

Corticothalamic feedback excitation specifically amplifies spindle-burst oscillations

During the period of stage III retinal waves, visual responses can be evoked in retina (through closed eyelids) and these are transmitted to VC (Colonnese et al., 2010). Until just before eye-opening, visual responses have an immature structure that consists of two distinct phases: an initial response composed of 'early gamma oscillations' (EGOs) (Khazipov et al., 2013b) followed by a secondary response consisting of spindle-bursts (Colonnese et al., 2010). We used this pattern to examine the differential role of corticothalamic feedback on these two prominent early activity patterns, as well as in the transition to the adult pattern. P9-11 LGN visual responses also consisted of early-gamma (30–50 Hz) followed by spindle-burst oscillations (8–30 Hz) (Figure 5B). Silencing VC reduced spike rates in LGN during both the primary and secondary responses (−46.2 ± 4.8% and −48.7 ± 5.8% respectively) (Figure 5D,F), but reduced the power of spike-rate oscillations only for spindle-burst oscillations (Figure 5G). These results confirm the strong amplification role of early corticothalamic feedback, and specifically implicate corticothalamic excitation in the generation of spindle-bursts, but not EGOs.

Figure 5

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At P13-14 visual responses in LGN were shorter and consisted of a rapid, non-oscillatory primary response, and greatly reduced secondary response (Figure 5C). This is identical to changes observed in VC (Colonnese et al., 2010). As observed for spontaneous activity, silencing VC at this age no longer reduced LGN activity. Instead, it caused a non-significant increase in the evoked spike-rate during the primary response (+15.1 ± 13.3%) and a significant increase in the secondary response (+48.5 ± 9.0%) (Figure 5F). These results show that the switch in corticothalamic feedback from functionally excitatory to inhibitory is not limited to spontaneous activity. They further show that corticothalamic feedback is not necessary for the loss of evoked gamma and spindle-bursts from visual responses at P13, which instead appear to depend on altered circuitry in LGN and retina.

We used pharmacological silencing and optogenetic stimulation in unanesthetized rats in vivo to show a change in the functional role of corticothalamic projections during development. Before vision, when spontaneous retinal waves instruct circuit formation (Huberman et al., 2008), the corticothalamic projection provides excitatory feedback amplification to thalamus. Although retina initiates activity in central visual circuits, retinal waves alone provide as little as 20% of the total drive. Corticothalamic feedback amplification accounts for the remaining 80%, effectively gating transmission of retinal waves in thalamus. During the second post-natal week corticothalamic excitation not only amplifies, but also synchronizes, thalamic firing, effectively conditioning its own input. Our results show that the transmission of early spontaneous activity is not simply feed-forward, and that feedback circuits can have specialized developmental properties that ensure the reliable transmission of early activity from the periphery to the cortex. The mechanism is the delayed development of inhibitory recruitment by the corticothalamic projection. This is a common observation in developing circuits (Le Magueresse and Monyer, 2013), yet the functional significance has been difficult to prove.

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Author details

1. Yasunobu Murata

   1. Department of Pharmacology and Physiology, George Washington University, Washington, United States
   2. Institute for Neuroscience, George Washington University, Washington, United States

   Contribution

   YM, Designed the experiments and wrote the paper, Performed and analyzed the experiments

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0001-5757-2497

2. Matthew T Colonnese

   1. Department of Pharmacology and Physiology, George Washington University, Washington, United States
   2. Institute for Neuroscience, George Washington University, Washington, United States

   Contribution

   MTC, Designed the experiments and wrote the paper, Analysis and interpretation of data

   For correspondence

   colonnese@gwu.edu

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-2480-1270

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