Subplate Cells: Amplifiers of Neuronal Activity in the Developing Cerebral Cortex

Due to their unique structural and functional properties, subplate cells are ideally suited to function as important amplifying units within the developing neocortical circuit. Subplate neurons have extensive dendritic and axonal ramifications and relatively mature functional properties, i.e. their action potential firing can exceed frequencies of 40 Hz. At earliest stages of corticogenesis subplate cells receive functional synaptic inputs from the thalamus and from other cortical and non-cortical sources. Glutamatergic and depolarizing GABAergic inputs arise from cortical neurons and neuromodulatory inputs arise from the basal forebrain and other sources. Activation of postsynaptic metabotropic receptors, i.e. muscarinic receptors, elicits in subplate neurons oscillatory burst discharges which are transmitted via electrical and chemical synapses to neighbouring subplate cells and to immature neurons in the cortical plate. The tonic non-synaptic release of GABA from GABAergic subplate cells facilitates the generation of burst discharges. These cellular bursts are amplified by prominent gap junction coupling in the subplate and cortical plate, thereby eliciting 10–20 Hz oscillations in a local columnar network. Thus, we propose that neuronal networks are organized at earliest stages in a gap junction coupled columnar syncytium. We postulate that the subplate does not only serve as a transient relay station for afferent inputs, but rather as an active element amplifying the afferent and intracortical activity

Prenatal Immune and Endocrine Modulators of Offspring's Brain Development and Cognitive Functions Later in Life

Milestones of brain development in mammals are completed before birth, which provide the prerequisite for cognitive and intellectual performances of the offspring. Prenatal challenges, such as maternal stress experience or infections, have been linked to impaired cognitive development, poor intellectual performances as well as neurodevelopmental and psychiatric disorders in the offspring later in life. Fetal microglial cells may be the target of such challenges and could be functionally modified by maternal markers. Maternal markers can cross the placenta and reach the fetus, a phenomenon commonly referred to as "vertical transfer." These maternal markers include hormones, such as glucocorticoids, and also maternal immune cells and cytokines, all of which can be altered in response to prenatal challenges. Whilst it is difficult to discriminate between the maternal or fetal origin of glucocorticoids and cytokines in the offspring, immune cells of maternal origin-although low in frequency-can be clearly set apart from offspring's cells in the fetal and adult brain. To date, insights into the functional role of these cells are limited, but it is emergingly recognized that these maternal microchimeric cells may affect fetal brain development, as well as post-natal cognitive performances and behavior. Moreover, the inheritance of vertically transferred cells across generations has been proposed, yielding to the presence of a microchiome in individuals. Hence, it will be one of the scientific challenges in the field of neuroimmunology to identify the functional role of maternal microchimeric cells as well as the brain microchiome. Maternal microchimeric cells, along with hormones and cytokines, may induce epigenetic changes in the fetal brain. Recent data underpin that brain development in response to prenatal stress challenges can be altered across several generations, independent of a genetic predisposition, supporting an epigenetic inheritance. We here discuss how fetal brain development and offspring's cognitive functions later in life is modulated in the turnstile of prenatal challenges by introducing novel and recently emerging pathway, involving maternal hormones and immune markers

Coupled Oscillations Mediate Directed Interactions between Prefrontal Cortex and Hippocampus of the Neonatal Rat

SummaryThe coactivation of prefrontal and hippocampal networks in oscillatory rhythms is critical for precise information flow in mnemonic and executive tasks, yet the mechanisms governing its development are still unknown. Here, we demonstrate that already in neonatal rats, patterns of discontinuous oscillatory activity precisely entrain the firing of prefrontal neurons and have distinct spatial and temporal organization over cingulate and prelimbic cortices. Moreover, we show that hippocampal theta bursts drive the generation of neonatal prefrontal oscillations by phase-locking the neuronal firing via axonal pathways. Consequently, functional impairment of the hippocampus reduces the prefrontal activity. With ongoing maturation continuous theta-gamma oscillations emerge and mutually entrain the prejuvenile prefrontal-hippocampal networks. Thus, theta-modulated communication within developing prefrontal-hippocampal networks may be relevant for circuitry refinement and maturation of functional units underlying information storage at adulthood

Balancing family with a successful career in neuroscience.

After years of hard work as a student and postdoc, stressful negotiations and restless nights of agony regarding your academic future, you managed to secure a Principal Investigator (PI) position and establish your own laboratory. And just when you thought you could relax a bit and enjoy some time with your family, or start a family, you find yourself facing massive levels of responsibility added to your research, that demand most of your time and energy. The challenge to balance a successful career with a happy family life is not a trivial one.The FENS‐Kavli Network of Excellence is supported by FENS, the Kavli Foundation, Alzheimer's Research UK, the European Molecular Biology Organization (EMBO) and Roche. P.P. acknowledges funding from the European Research Council (StG 311435 dEMORY). J.G. is supported by the European Research Council (StG 678832 REMOTE MEMORY TRACES), an MQ fellow award, the Swiss National Science Foundation, the National Competence Center for Research in Switzerland SYNAPSY, the SYNAPSIS Foundation, the Béatrice Ederer‐Weber Stiftung, the Alzheimer's Association as well as by an Independent Investigator Award from the Brain and Behavior Research Foundation. I.H.‐O. is supported by the ERC Consolidator Grant CoG 681577 PSYCHOCELL. D.B. is supported by the Wellcome Trust. G.L.‐B. is supported by the European Research Council, ERC‐2014‐CoG 647012 and the Spanish MINECO BFU2012‐34298 grant

Thalamic and Entorhinal Network Activity Differently Modulates the Functional Development of Prefrontal-Hippocampal Interactions.

Precise information flow during mnemonic and executive tasks requires the coactivation of adult prefrontal and hippocampal networks in oscillatory rhythms. This interplay emerges early in life, most likely as an anticipatory template of later cognitive performance. At neonatal age, hippocampal theta bursts drive the generation of prefrontal theta-gamma oscillations. In the absence of direct reciprocal interactions, the question arises of which feedback mechanisms control the early entrainment of prefrontal-hippocampal networks. Here, we demonstrate that prefrontal-hippocampal activity couples with discontinuous theta oscillations and neuronal firing in both lateral entorhinal cortex and ventral midline thalamic nuclei of neonatal rats. However, these two brain areas have different contributions to the neonatal long-range communication. The entorhinal cortex mainly modulates the hippocampal activity via direct axonal projections. In contrast, thalamic theta bursts are controlled by the prefrontal cortex via mutual projections and contribute to hippocampal activity. Thus, the neonatal prefrontal cortex modulates the level of hippocampal activation by directed interactions with the ventral midline thalamus. Similar to the adult task-related communication, theta-band activity ensures the feedback control of long-range coupling in the developing brain.Significance statementMemories are encoded by finely tuned interactions within large-scale neuronal networks. This cognitive performance is not inherited, but progressively matures in relationship with the establishment of long-range coupling in the immature brain. The hippocampus initiates and unidirectionally drives the oscillatory entrainment of neonatal prefrontal cortex, yet feedback interactions that precisely control this early communication are still unresolved. Here, we identified distinct roles of entorhinal cortex and ventral midline thalamus for the functional development of prefrontal-hippocampal interactions. While entorhinal oscillations modulate the hippocampal activity by timing the neuronal firing via monosynaptic afferents, thalamic nuclei act as a relay station routing prefrontal activation back to hippocampus. Understanding the mechanisms of network maturation represents the prerequisite for assessing circuit dysfunction in neurodevelopmental disorders

Prenatal Immune and Endocrine Modulators of Offspring's Brain Development and Cognitive Functions Later in Life

Milestones of brain development in mammals are completed before birth, which provide the prerequisite for cognitive and intellectual performances of the offspring. Prenatal challenges, such as maternal stress experience or infections, have been linked to impaired cognitive development, poor intellectual performances as well as neurodevelopmental and psychiatric disorders in the offspring later in life. Fetal microglial cells may be the target of such challenges and could be functionally modified by maternal markers. Maternal markers can cross the placenta and reach the fetus, a phenomenon commonly referred to as “vertical transfer.” These maternal markers include hormones, such as glucocorticoids, and also maternal immune cells and cytokines, all of which can be altered in response to prenatal challenges. Whilst it is difficult to discriminate between the maternal or fetal origin of glucocorticoids and cytokines in the offspring, immune cells of maternal origin—although low in frequency—can be clearly set apart from offspring's cells in the fetal and adult brain. To date, insights into the functional role of these cells are limited, but it is emergingly recognized that these maternal microchimeric cells may affect fetal brain development, as well as post-natal cognitive performances and behavior. Moreover, the inheritance of vertically transferred cells across generations has been proposed, yielding to the presence of a microchiome in individuals. Hence, it will be one of the scientific challenges in the field of neuroimmunology to identify the functional role of maternal microchimeric cells as well as the brain microchiome. Maternal microchimeric cells, along with hormones and cytokines, may induce epigenetic changes in the fetal brain. Recent data underpin that brain development in response to prenatal stress challenges can be altered across several generations, independent of a genetic predisposition, supporting an epigenetic inheritance. We here discuss how fetal brain development and offspring's cognitive functions later in life is modulated in the turnstile of prenatal challenges by introducing novel and recently emerging pathway, involving maternal hormones and immune markers

Synchronous Infra-Slow Oscillations Organize Ensembles of Accessory Olfactory Bulb Projection Neurons into Distinct Microcircuits

The accessory olfactory system controls social and sexual behavior. In the mouse accessory olfactory bulb, the first central stage of information processing along the accessory olfactory pathway, projection neurons (mitral cells) display infra-slow oscillatory discharge with remarkable periodicity. The physiological mechanisms that underlie this default output state, however, remain controversial. Moreover, whether such rhythmic infra-slow activity patterns exist in awake behaving mice and whether such activity reflects the functional organization of the accessory olfactory bulb circuitry remain unclear. Here, we hypothesize that mitral cell ensembles form synchronized microcircuits that subdivide the accessory olfactory bulb into segregated functional clusters. We use a miniature microscope to image the Ca2+ dynamics within the apical dendritic compartments of large mitral cell ensembles in vivo. We show that infra-slow periodic patterns of concerted neural activity, indeed, reflect the idle state of accessory olfactory bulb output in awake male and female mice. Ca2+ activity profiles are distinct and glomerulus-specific. Confocal time-lapse imaging in acute slices reveals that groups of mitral cells assemble into microcircuits that exhibit correlated Ca2+ signals. Moreover, electrophysiological profiling of synaptic connectivity indicates functional coupling between mitral cells. Our results suggest that both intrinsically rhythmogenic neurons and neurons entrained by fast synaptic drive are key elements in organizing the accessory olfactory bulb into functional microcircuits, each characterized by a distinct default pattern of infra-slow rhythmicity

From Shortage to Surge : A Developmental Switch in Hippocampal-Prefrontal Coupling in a Gene-Environment Model of Neuropsychiatric Disorders

Cognitive deficits represent a major burden of neuropsychiatric disorders and result in part from abnormal communication within hippocampal-prefrontal circuits. While it has been hypothesized that this network dysfunction arises during development, long before the first clinical symptoms, experimental evidence is still missing. Here, we show that pre-juvenile mice mimicking genetic and environmental risk factors of disease (dual-hit GE mice) have poorer recognition memory that correlates with augmented coupling by synchrony and stronger directed interactions between prefrontal cortex and hippocampus. The network dysfunction emerges already during neonatal development, yet it initially consists in a diminished hippocampal theta drive and consequently, a weaker and disorganized entrainment of local prefrontal circuits in discontinuous oscillatory activity in dual-hit GE mice when compared with controls. Thus, impaired maturation of functional communication within hippocampal-prefrontal networks switching from hypo- to hyper-coupling may represent a mechanism underlying the pathophysiology of cognitive deficits in neuropsychiatric disorders.Peer reviewe

Neural Correlates of Anesthesia in Newborn Mice and Humans

Monitoring the hypnotic component of anesthesia during surgeries is critical to prevent intraoperative awareness and reduce adverse side effects. For this purpose, electroencephalographic (EEG) methods complementing measures of autonomic functions and behavioral responses are in use in clinical practice. However, in human neonates and infants existing methods may be unreliable and the correlation between brain activity and anesthetic depth is still poorly understood. Here, we characterized the effects of different anesthetics on brain activity in neonatal mice and developed machine learning approaches to identify electrophysiological features predicting inspired or end-tidal anesthetic concentration as a proxy for anesthetic depth. We show that similar features from EEG recordings can be applied to predict anesthetic concentration in neonatal mice and humans. These results might support a novel strategy to monitor anesthetic depth in human newborns

An information-theoretic quantification of the content of communication between brain regions

Quantifying the amount, content and direction of communication between brain regions is key to understanding brain function. Traditional methods to analyze brain activity based on the Wiener-Granger causality principle quantify the overall information propagated by neural activity between simultaneously recorded brain regions, but do not reveal the information flow about specific features of interest (such as sensory stimuli). Here, we develop a new information theoretic measure termed Feature-specific Information Transfer (FIT), quantifying how much information about a specific feature flows between two regions. FIT merges the Wiener-Granger causality principle with information-content specificity. We first derive FIT and prove analytically its key properties. We then illustrate and test them with simulations of neural activity, demonstrating that FIT identifies, within the total information propagated between regions, the information that is transmitted about specific features. We then analyze three neural datasets obtained with different recording methods, magneto- and electro-encephalography, and spiking activity, to demonstrate the ability of FIT to uncover the content and direction of information flow between brain regions beyond what can be discerned with traditional analytical methods. FIT can improve our understanding of how brain regions communicate by uncovering previously unaddressed feature-specific information flow