An excitatory cortical feedback loop gates retinal wave transmission in rodent thalamus

Spontaneous retinal waves are critical for the development of receptive fields in visual thalamus (LGN) and cortex (VC). Despite a detailed understanding of the circuit specializations in retina that generate waves, whether central circuit specializations also exist to control their propagation through visual pathways of the brain is unknown. Here we identify a developmentally transient, corticothalamic amplification of retinal drive to thalamus as a mechanism for retinal wave transmission in the infant rat brain. During the period of retinal waves, corticothalamic connections excite LGN, rather than driving feedforward inhibition as observed in the adult. This creates an excitatory feedback loop that gates retinal wave transmission through the LGN. This cortical multiplication of retinal wave input ends just prior to eye-opening, as cortex begins to inhibit LGN. Our results show that the early retino-thalamo-cortical circuit uses developmentally specialized feedback amplification to ensure powerful, high-fidelity transmission of retinal activity despite immature connectivity

Development of Activity in the Mouse Visual Cortex.

A comprehensive developmental timeline of activity in the mouse cortex in vivo is lacking. Understanding the activity changes that accompany synapse and circuit formation is important to understand the mechanisms by which activity molds circuits and would help to identify critical checkpoints for normal development. To identify key principles of cortical activity maturation, we systematically tracked spontaneous and sensory-evoked activity with extracellular recordings of primary visual cortex (V1) in nonanesthetized mice. During the first postnatal week (postnatal days P4–P7), V1 was not visually responsive and exhibited long (>10 s) periods of network silence. Activation consisted exclusively of “slow-activity transients,” 2–10 s periods of 6–10 Hz “spindle-burst' oscillations; the response to spontaneous retinal waves. By tracking daily changes in this activity, two key components of spontaneous activity maturation were revealed: (1) spindle-burst frequency acceleration (eventually becoming the 20–50 Hz broadband activity caused by the asynchronous state) and (2) “filling-in” of silent periods with low-frequency (2–4 Hz) activity (beginning on P10 and complete by P13). These two changes are sufficient to create the adult-like pattern of continuous activity, alternation between fast-asynchronous and slow-synchronous activity, by eye opening. Visual responses emerged on P8 as evoked spindle-bursts and neuronal firing with a signal-to-noise ratio higher than adult. Both were eliminated by eye opening, leaving only the mature, short-latency response. These results identify the developmental origins of mature cortical activity and implicate the period before eye opening as a critical checkpoint. By providing a systematic description of electrical activity development, we establish the murine visual cortex as a model for the electroencephalographic development of fetal humans. SIGNIFICANCE STATEMENT Cortical activity is an important indicator of long-term health and survival in preterm infants and molds circuit formation, but gaps remain in our understanding of the origin and normal progression of this activity in the developing cortex. We aimed to rectify this by monitoring daily changes in cortical activity in the nonanesthetized mouse, an important preclinical model of disease and development. At ages approximately equivalent to normal human term birth, mouse cortex exhibits primarily network silence, with spontaneous “spindle bursts” as the only form of activity. In contrast, mature cortex is noisy, alternating between asynchronous/discontinuous and synchronous/continuous states. This work identifies the key processes that produce this maturation and provides a normative reference for murine-based studies of cortical circuit development

A Synaptic Strategy for Consolidation of Convergent Visuotopic Maps

The mechanisms by which experience guides refinement of converging afferent pathways are poorly understood. We describe a vision-driven refinement of corticocollicular inputs that determines the consolidation of retinal and visual cortical (VC) synapses on individual neurons in the superficial superior colliculus (sSC). Highly refined corticocollicular terminals form 1–2 days after eye-opening (EO), accompanied by VC-dependent filopodia sprouting on proximal dendrites, and PSD-95 and VC-dependent quadrupling of functional synapses. Delayed EO eliminates synapses, corticocollicular terminals, and spines on VC-recipient dendrites. Awake recordings after EO show that VC and retina cooperate to activate sSC neurons, and VC light responses precede sSC responses within intervals promoting potentiation. Eyelid closure is associated with more protracted cortical visual responses, causing the majority of VC spikes to follow those of the colliculus. These data implicate spike-timing plasticity as a mechanism for cortical input survival, and support a cooperative strategy for retinal and cortical coinnervation of the sSC.National Institutes of Health (U.S.) (Grant EY006039

Thalamic inhibitory circuits and network activity development

© 2018 Elsevier B.V. Inhibitory circuits in thalamus and cortex shape the major activity patterns observed by electroencephalogram (EEG) in the adult brain. Their delayed maturation and circuit integration, relative to excitatory neurons, suggest inhibitory neuronal development could be responsible for the onset of mature thalamocortical activity. Indeed, the immature brain lacks many inhibition-dependent activity patterns, such as slow-waves, delta oscillations and sleep-spindles, and instead expresses other unique oscillatory activities in multiple species including humans. Thalamus contributes significantly to the generation of these early oscillations. Compared to the abundance of studies on the development of inhibition in cortex, however, the maturation of thalamic inhibition is poorly understood. Here we review developmental changes in the neuronal and circuit properties of the thalamic relay and its interconnected inhibitory thalamic reticular nucleus (TRN) both in vitro and in vivo, and discuss their potential contribution to early network activity and its maturation. While much is unknown, we argue that weak inhibitory function in the developing thalamus allows for amplification of thalamocortical activity that supports the generation of early oscillations. The available evidence suggests that the developmental acquisition of critical thalamic oscillations such as slow-waves and sleep-spindles is driven by maturation of the TRN. Further studies to elucidate thalamic GABAergic circuit formation in relation to thalamocortical network function would help us better understand normal as well as pathological brain development

Thalamus controls development and expression of arousal states in visual cortex

© 2018 the authors. Two major checkpoints of development in cerebral cortex are the acquisition of continuous spontaneous activity and the modulation of this activity by behavioral state. Despite the critical importance of these functions, the circuit mechanisms of their development remain unknown. Here we use the rodent visual system as a model to test the hypothesis that the locus of circuit change responsible for the developmental acquisition of continuity and state dependence measured in sensory cortex is relay thalamus, rather than the local cortical circuitry or the interconnectivity of the two structures. We conducted simultaneous recordings in the dorsal lateral geniculate nucleus (dLGN) and primary visual cortex (VC) of awake, head-fixed male and female rats using linear multielectrode arrays throughout early development. We find that activity in dLGN becomes continuous and positively correlated with movement (a measure of state dependence) on P13, the same day as VC, and that these properties are not dependent on VC activity. By contrast, silencing dLGN after P13 causes activity in VC to become discontinuous and movement to suppress, rather than augment, cortical firing, effectively reversing development. Thalamic bursting, a core characteristic of non-aroused states, emerged later, on P16, suggesting these processes are developmentally independent. Together our results indicate that cellular or circuit changes in relay thalamus are critical drivers for the maturation of background activity, which occurs around term in humans

GABAergic interneurons excite neonatal hippocampus in vivo

© 2020 The Authors. GABAergic interneurons are proposed to be critical for early activity and synapse formation by directly exciting, rather than inhibiting, neurons in developing hippocampus and neocortex. However, the role of GABAergic neurons in the generation of neonatal network activity has not been tested in vivo, and recent studies have challenged the excitatory nature of early GABA. By locally manipulating interneuron activity in unanesthetized neonatal mice, we show that GABAergic neurons are excitatory in CA1 hippocampus at postnatal day 3 (P3) and are responsible for most of the spontaneous firing of pyramidal cells at that age. Hippocampal interneurons become inhibitory by P7, whereas visual cortex interneurons are already inhibitory by P3 and remain so throughout development. These regional and age-specific differences are the result of a change in chloride reversal potential, because direct activation of light-gated anion channels in glutamatergic neurons drives CA1 firing at P3, but silences it at P7 in CA1, and at all ages in visual cortex. This study in the intact brain reveals that GABAergic interneuron excitation is essential for network activity in neonatal hippocampus and confirms that visual cortical interneurons are inhibitory throughout early postnatal development

cFOS as a biomarker of activity maturation in the hippocampal formation

We explored the potential for cFOS expression as a marker of functional development of resting-state waking activity in the extended network of the hippocampus and entorhinal cortex. We examined sleeping and awake mice at (P)ostnatal days 5, 9, 13, and 17 as well as in adulthood. We find that cFOS expression is state-dependent even at 5 days old, with reliable staining occurring only in the awake mice. Even during waking, cFOS expression was rare and weak at P5. The septal nuclei, entorhinal cortex layer (L)2, and anterodorsal thalamus were exceptional in that they had robust cFOS expression at P5 that was similar to or greater than in adulthood. Significant P5 expression was also observed in the dentate gyrus, entorhinal cortex L6, postsubiculum L4-6, ventral subiculum, supramammillary nucleus, and posterior hypothalamic nucleus. The expression in these regions grew stronger with age, and the expression in new regions was added progressively at P9 and P13 by which point the overall expression pattern in many regions was qualitatively similar to the adult. Six regions-CA1, dorsal subiculum, postsubiculum L2-3, reuniens nucleus, and perirhinal and postrhinal cortices-were very late developing, mostly achieving adult levels only after P17. Our findings support a number of developmental principles. First, early spontaneous activity patterns induced by muscle twitches during sleep do not induce robust cFOS expression in the extended hippocampal network. Second, the development of cFOS expression follows the progressive activation along the trisynaptic circuit, rather than birth date or cellular maturation. Third, we reveal components of the egocentric head-direction and theta-rhythm circuits as the earliest cFOS active circuits in the forebrain. Our results suggest that cFOS staining may provide a reliable and sensitive biomarker for hippocampal formation activity development, particularly in regard to the attainment of a normal waking state and synchronizing rhythms such as theta and gamma

GABAergic interneurons excite neonatal hippocampus in vivo

© 2020 The Authors. GABAergic interneurons are proposed to be critical for early activity and synapse formation by directly exciting, rather than inhibiting, neurons in developing hippocampus and neocortex. However, the role of GABAergic neurons in the generation of neonatal network activity has not been tested in vivo, and recent studies have challenged the excitatory nature of early GABA. By locally manipulating interneuron activity in unanesthetized neonatal mice, we show that GABAergic neurons are excitatory in CA1 hippocampus at postnatal day 3 (P3) and are responsible for most of the spontaneous firing of pyramidal cells at that age. Hippocampal interneurons become inhibitory by P7, whereas visual cortex interneurons are already inhibitory by P3 and remain so throughout development. These regional and age-specific differences are the result of a change in chloride reversal potential, because direct activation of light-gated anion channels in glutamatergic neurons drives CA1 firing at P3, but silences it at P7 in CA1, and at all ages in visual cortex. This study in the intact brain reveals that GABAergic interneuron excitation is essential for network activity in neonatal hippocampus and confirms that visual cortical interneurons are inhibitory throughout early postnatal development

Thalamocortical function in developing sensory circuits

© 2018 Elsevier Ltd Thalamocortical activity patterns, both spontaneous and evoked, undergo a dramatic shift in preparation for the onset of rich sensory experience (e.g. birth in humans; eye-opening in rodents). This change is the result of a switch from thalamocortical circuits tuned for transmission of spontaneous bursting in sense organs, to circuits capable of high resolution, active sensory processing. Early ‘pre-sensory’ tuning uses amplification generated by corticothalamic excitatory feedback and early-born subplate neurons to ensure transmission of bursts, at the expense of stimulus discrimination. The switch to sensory circuits is due, at least in part, to the coordinated remodeling of inhibitory circuits in thalamus and cortex. Appreciation of the distinct rules that govern early circuit function can, and should, inform translational studies of genetic and acquired developmental dysfunction