Dexmedetomidine as a Short-Use Analgesia for the Immature Nervous System.

Pain management in neonates continues to be a challenge. Diverse therapies are available that cause loss of pain sensitivity. However, because of side effects, the search for better options remains open. Dexmedetomidine is a promising drug; it has shown high efficacy with a good safety profile in sedation and analgesia in the immature nervous system. Though dexmedetomidine is already in use for pain control in neonates (including premature neonates) and infants as an adjunct to other anesthetics, the question remains whether it affects the neuronal activity patterning that is critical for development of the immature nervous system. In this study, using the neonatal rat as a model, the pharmacodynamic effects of dexmedetomidine on the nervous and cardiorespiratory systems were studied. Our results showed that dexmedetomidine has pronounced analgesic effects in the neonatal rat pups, and also weakly modified both the immature network patterns of cortical and hippocampal activity and the physiology of sleep cycles. Though the respiration and heart rates were slightly reduced after dexmedetomidine administration, it might be considered as the preferential independent short-term therapy for pain management in the immature and developing brain.

Early suppression of excitability in subcortical band heterotopia modifies epileptogenesis in rats.

Malformations of cortical development represent a major cause of epilepsy in childhood. However, the pathological substrate and dynamic changes leading to the development and progression of epilepsy remain unclear. Here, we characterized an etiology-relevant rat model of subcortical band heterotopia (SBH), a diffuse type of cortical malformation associated with drug-resistant seizures in humans. We used longitudinal electrographic recordings to monitor the age-dependent evolution of epileptiform discharges during the course of epileptogenesis in this model. We found both quantitative and qualitative age-related changes in seizures properties and patterns, accompanying a gradual progression towards a fully developed seizure pattern seen in adulthood. We also dissected the relative contribution of the band heterotopia and the overlying cortex to the development and age-dependent progression of epilepsy using timed and spatially targeted manipulation of neuronal excitability. We found that an early suppression of neuronal excitability in SBH slows down epileptogenesis in juvenile rats, whereas epileptogenesis is paradoxically exacerbated when excitability is suppressed in the overlying cortex. However, in rats with active epilepsy, similar manipulations of excitability have no effect on chronic spontaneous seizures. Together, our data support the notion that complex developmental alterations occurring in both the SBH and the overlying cortex concur to creating pathogenic circuits prone to generate seizures. Our study also suggests that early and targeted interventions could potentially influence the course of these altered developmental trajectories, and favorably modify epileptogenesis in malformations of cortical development.

Simple and Efficient 3D-Printed Superfusion Chamber for Electrophysiological and Neuroimaging Recordings In Vivo.

In vitro and in vivo experimentation in the central nervous system are effective approaches to study its functioning. Manipulations in vitro are characterized by easy experimental control and stable experimental conditions. However, transferring these advantages to in vivo research remains technically and ethically challenging, preventing many research teams from acquiring critical recordings in their animal models. In order to transfer the benefits of in vitro experimentation to in vivo experimentation, we developed a suite of 3D-printed tools (a superfusion chamber with an independent brain presser and animal stand). Using the immature rat barrel cortex as a model, we show that our set of tools (further "superfusion preparation") provides stable conditions for electrophysiological and neuroimaging recordings in the neonatal rat neocortex in vivo Highly correlated intracellular and extracellular activity was recorded during spontaneous and evoked cortical activity, supporting the possibility of simultaneous long-lasting electrophysiological recordings from a single cortical column in vivo The optical intrinsic signal of evoked cortical responses was also recorded from the skull-free neocortex, suggesting the effective combination of the superfusion preparation with neuroimaging approaches. Modulation of immature activity by epicortical application of pharmacological agents via superfusion equally supports the use of the superfused cortex preparation in pharmacological screening. In addition to high efficiency (in affordability, reliability, and ease of use in vivo), the 3D-printed set of tools developed should reduce animal use, supporting the 3Rs principle (Replacement, Reduction, and Refinement) of ethical use of animals.

The rapid developmental rise of somatic inhibition disengages hippocampal dynamics from self-motion.

Early electrophysiological brain oscillations recorded in preterm babies and newborn rodents are initially mostly driven by bottom-up sensorimotor activity and only later can detach from external inputs. This is a hallmark of most developing brain areas, including the hippocampus, which, in the adult brain, functions in integrating external inputs onto internal dynamics. Such developmental disengagement from external inputs is likely a fundamental step for the proper development of cognitive internal models. Despite its importance, the developmental timeline and circuit basis for this disengagement remain unknown. To address this issue, we have investigated the daily evolution of CA1 dynamics and underlying circuits during the first two postnatal weeks of mouse development using two-photon calcium imaging in non-anesthetized pups. We show that the first postnatal week ends with an abrupt shift in the representation of self-motion in CA1. Indeed, most CA1 pyramidal cells switch from activated to inhibited by self-generated movements at the end of the first postnatal week, whereas the majority of GABAergic neurons remain positively modulated throughout this period. This rapid switch occurs within 2 days and follows the rapid anatomical and functional surge of local somatic GABAergic innervation. The observed change in dynamics is consistent with a two-population model undergoing a strengthening of inhibition. We propose that this abrupt developmental transition inaugurates the emergence of internal hippocampal dynamics.

Horizontal Synchronization of Neuronal Activity in the Barrel Cortex of the Neonatal Rat by Spindle-Burst Oscillations.

During development, activity in the somatosensory cortex is characterized by intermittent oscillatory bursts at gamma (early gamma-oscillations, EGOs) and alpha-beta (spindle-bursts, SBs) frequencies. Here, we explored the topography of EGOs and SBs in the neighbor barrels of the whisker-related barrel cortex of neonatal rats (P4-7) during responses evoked by simultaneous activation of multiple whiskers as it occurs during natural conditions. We found that brief simultaneous deflection of all whiskers evoked complex neuronal responses comprised of EGOs and SBs. In contrast to EGOs, that specifically synchronized neuronal activity in each individual barrel, SBs efficiently synchronized activity between neighboring barrels. After plucking a single whisker, synchronous stimulation of spared whiskers evoked EGO-lacking responses in the whisker-deprived barrel, even though the remaining neuronal activity was synchronized by SBs in neighboring barrels. Thus, EGOs specifically support topographic synchronization of neuronal activity within barrels, whereas SBs support horizontal synchronization between neighboring barrels during stimulation of multiple whiskers. We suggest that these two co-existing activity patterns coordinate activity-dependent formation of topographic maps and support the emergence of integrative functions in the primary somatosensory cortex during the critical period of somatosensory maps development.

Developmental Changes in Sensory-Evoked Optical Intrinsic Signals in the Rat Barrel Cortex.

Optical Intrinsic Signal imaging (OISi) is a powerful technique for optical brain studies. OIS mainly reflects the hemodynamic response (HR) and metabolism, but it may also involve changes in tissue light scattering (LS) caused by transient cellular swelling in the active tissue. Here, we explored the developmental features of sensory-evoked OIS in the rat barrel cortex during the first 3 months after birth. Multispectral OISi revealed that two temporally distinct components contribute to the neonatal OIS: an early phase of LS followed by a late phase of HR. The contribution of LS to the early response was also evidenced by an increase in light transmission through the active barrel. The early OIS phase correlated in time and amplitude with the sensory-evoked electrophysiological response. Application of the Modified Beer-Lambert Law (MBLL) to the OIS data revealed that HR during the early phase involved only a slight decrease in blood oxygenation without any change in blood volume. In contrast, HR during the late phase manifested an adult-like increase in blood volume and oxygenation. During development, the peak time of the delayed HR progressively shortened with age, nearly reaching the stimulus onset and overlapping with the early LS phase by the fourth postnatal week. Thus, LS contributes to the sensory-evoked OIS in the barrel cortex of rats at all ages, and it dominates the early OIS phase in neonatal rats due to delayed HR. Our results are also consistent with the delayed blood oxygen level dependent (BOLD) signal in human preterm infants.