Biology subjects

Hanganu-Opatz, I. L.

Publications and source records attributed to Hanganu-Opatz, I. L..

At least 19 recordsLinked to original sources

bioRxiv2025

Mapping prefrontal afferents along development

The medial prefrontal cortex (mPFC) acts as a hub for cognitive, emotional, and social processes, integrating neuronal inputs from numerous brain regions. Knowledge on the processes underlying formation and myelination of prefrontal afferents is essential for a comprehensive understanding of the emergence, maturation, and refinement of mPFC-dependent behaviors. However, despite detailed investigation of long-range projections to the mPFC in the adult brain, little is known about their maturation. Here, we use retrograde labeling, light-sheet imaging, and automatic cell segmentation to quantify afferent projections to the mPFC from neonatal to adult age. We show that densities of ipsi- and contralateral prefrontal afferents change along development from a widespread bilateral distribution at neonatal age to a predominantly ipsilateral organization. Furthermore, myelination of interhemispheric prefrontal afferents starts only after the decline of neonatal contralateral projections and is followed by temporally elevated projection densities from limbic brain regions. Overall, these distinct developmental dynamics of prefrontal afferents might have major implications for the maturation of mPFC-dependent functional and behavioral outputs.

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bioRxiv2025

iSTTC: a robust method for accurate estimation of intrinsic neural timescales from single-unit recordings

Intrinsic neural timescales (ITs) are an emerging measure of how neural circuits integrate information over time. ITs are dynamically regulated by behavioral context and cognitive demands, making them suitable for mapping high-level cognitive phenomena onto the underlying neural computations. In particular, IT measurements derived from single-unit activity (SUA) offer fine-grained resolution, critical for mechanistically linking individual neuron dynamics to cognition. However, current methods for estimating ITs from SUA suffer significant biases and instabilities, particularly when applied to sparse, noisy, or epoched neural spike data. Here, we introduce the intrinsic Spike Time Tiling Coefficient (iSTTC), a novel metric specifically developed to address these limitations. Leveraging synthetic and experimental single-unit recordings, we systematically assessed the performance of iSTTC relative to traditional approaches. Our findings demonstrate that iSTTC provides more accurate estimates of neural timescales across a wide range of conditions, reducing estimation error especially under challenging yet biologically relevant conditions. Crucially, iSTTC can be applied to both continuous and epoched data, overcoming a critical limitation of existing methods. Furthermore, iSTTC substantially relaxes inclusion criteria, increasing the fraction of neurons suitable for analysis and thereby improving the representativeness and robustness of IT measurements. The methodological advances introduced by iSTTC represent a substantial step forward in accurately capturing neural circuit dynamics, ultimately enhancing our ability to link neural mechanisms to cognitive phenomena.

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bioRxiv2025

Developmental embedding of parvalbumin interneurons drives local and crosshemispheric prefrontal gamma synchrony

Gamma oscillations are a pivotal trait of cortical cognitive processing. However, the ability to generate gamma oscillations evolves with age and requires cellular adjustments of the underlying neural networks. In the prefrontal cortex, gamma oscillations emerge relatively late compared to other cortical areas, yet the developmental mechanisms leading to the generation of adult-like gamma oscillations are poorly understood. Here, we combine bilateral in vivo electrophysiology and selective optogenetic manipulations of parvalbumin- (PV+) and somatostatin-positive (SOM+) interneurons in the mouse medial prefrontal cortex along late development to investigate their role for the age-dependent maturation of gamma oscillations. We show that crosshemispheric gamma synchrony strengthens with age, in line with the previously reported increase in local gamma power. Following a similar timeline, the inhibitory effect of PV+ interneurons emerges which start to functionally operate within the classical gamma frequency range from adolescence onwards. In contrast, SOM+ interneurons show no such age-dependent functional integration and display their beta oscillation modulating inhibitory effect across age. These data identify the SOM+ to PV+ interneuron switch as a mechanism of gamma ontogeny and emergence of crosshemispheric synchrony in the developing prefrontal cortex. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/653375v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1a78b6aorg.highwire.dtl.DTLVardef@b21464org.highwire.dtl.DTLVardef@158bad2org.highwire.dtl.DTLVardef@516706_HPS_FORMAT_FIGEXP M_FIG C_FIG

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bioRxiv2023

Protosequences in human cortical organoids model intrinsic states in the developing cortex

Neuronal firing sequences are thought to be the basic building blocks of neural coding and information broadcasting within the brain. However, when sequences emerge during neurodevelopment remains unknown. We demonstrate that structured firing sequences are present in spontaneous activity of human and murine brain organoids and ex vivo neonatal brain slices from the murine somatosensory cortex. We observed a balance between temporally rigid and flexible firing patterns that are emergent phenomena in human and murine brain organoids and early postnatal murine somatosensory cortex, but not in primary dissociated cortical cultures. Our findings suggest that temporal sequences do not arise in an experience-dependent manner, but are rather constrained by an innate preconfigured architecture established during neurogenesis. These findings highlight the potential for brain organoids to further explore how exogenous inputs can be used to refine neuronal circuits and enable new studies into the genetic mechanisms that govern assembly of functional circuitry during early human brain development.

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bioRxiv2023

Extreme distributions in the preconfigured developing brain

In the adult brain, structural and functional parameters, such as synaptic sizes and neuronal firing rates, follow right-skewed and heavy-tailed distributions. While this organization is thought of having significant implications, its development is still largely unknown. Here, we address this knowledge gap by investigating a large-scale dataset recorded from the prefrontal cortex (PFC) and the olfactory bulb of mice aged 4-60 postnatal days. We show that firing rates and pairwise correlations have a largely stable distribution shape over age, and that neural activity displays a small-world architecture. Moreover, early brain activity displays an oligarchical organization, i.e., neurons with high firing rates are likely to have hub-like properties. Leveraging neural network modeling, we show that analogously extremely distributed synaptic parameters are necessary to recapitulate the experimental data. Thus, functional and structural parameters in the developing brain are already extremely distributed, suggesting that this organization is preconfigured and not experience-dependent.

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bioRxiv2023

A developmental increase of inhibition promotes the emergence of hippocampal ripples

Sharp wave-ripples (SPW-Rs) are a hippocampal network phenomenon critical for memory consolidation and planning. SPW-Rs have been extensively studied in the adult brain, yet their developmental trajectory is poorly understood. While SPWs have been recorded in rodents shortly after birth, the time point and mechanisms of ripple emergence are still unclear. Here, we combine in vivo electrophysiology with optogenetics and chemogenetics in 4 to 12 days-old mice to address this knowledge gap. We show that ripples are robustly detected and induced by light stimulation of ChR2-transfected CA1 pyramidal neurons only from postnatal day (P) 10 onwards. Leveraging a spiking neural network model, we mechanistically link the maturation of inhibition and ripple emergence. We corroborate these findings by reducing ripple rate upon chemogenetic silencing of CA1 interneurons. Finally, we show that early SPW-Rs elicit a more robust prefrontal cortex response then SPWs lacking ripples. Thus, development of inhibition promotes ripples emergence.

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bioRxiv2023

Blood pressure pulsations modulate olfactory bulb neuronal activity via mechanosensitive ion channels

AbstractThe transmission of heartbeat through the cerebral vascular system is known to cause intracranial pressure pulsations. Here we describe that arterial pressure pulsations within the brain can directly modulate central neuronal activity. In a semi-intact rat brain preparation, pressure pulsations elicit correlated local field oscillations in the olfactory bulb (OB) that are sensitive to hypoxia and block of mechanosensitive channels. We find that mitral cell spiking activity is in part synchronized to these oscillations. Indeed, in awake animals the firing of a subset of OB neurons is entrained to heartbeat within [~] 20 ms. Several lines of evidence indicate the expression of a mechanosensitive ion channel within the mitral cell membranes, most likely Piezo2, implementing a pressure pulsation transduction pathway and thus baroreception within the OB. We propose that this intrinsic interoceptive mechanism modulates OB neuronal activity e.g. during arousal and also could influence brain activity on a wider scale.

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bioRxiv2022

Generation and propagation of network bursts in the basal ganglia exhibit dynamic changes during early postnatal development

The neonatal brain is characterised by intermittent bursts of oscillatory activity interspersed by relative silence. While these bursts of activity are well characterised for many cortical areas much less is known whether and how these propagate and interact with subcortical regions. Here, early network activity was recorded using silicon probes from the developing basal ganglia, including the motor/somatosensory cortex, dorsal striatum and intralaminar thalamus, during the first two postnatal weeks in mice. Using an unsupervised detection and classification method, two main classes of bursting activity were found, consisting of spindle bursts (SB) and nested gamma spindle bursts (NGB), which were characterised by oscillatory activity at respectively [~]10 Hz and [~]30 Hz. These bursts were reliably identified across all three brain structures but differed in their structural, spectral, and developmental characteristics. Coherence and cross-correlation analyses revealed that burst events often occur synchronously across different brain regions and were mostly of a similar type, especially between cortex and striatum, which also exhibited the strongest interactions as compared to other brain regions. Interestingly, the preferred frequency for these interactions suggested a developmental shift from initial lower frequencies to higher frequencies across development. Together, these results provide the first detailed description of early network activity within the developing basal ganglia and suggests that distinct brain regions drive and coordinate burst activity at different developmental stages.

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bioRxiv2021

Olfactory-driven beta band entrainment of limbic circuitry during neonatal development

Cognitive processing relies on the functional refinement of the limbic circuitry during the first two weeks of life. During this developmental period, when most sensory systems are still immature, the sense of olfaction acts as "door to the world", providing the main source of environmental inputs. However, it is unknown whether early olfactory processing shapes the activity in the limbic circuitry during neonatal development. Here, we address this question by combining simultaneous in vivo recordings from the olfactory bulb (OB), lateral entorhinal cortex (LEC), hippocampus (HP), and prefrontal cortex (PFC) with olfactory stimulation as well as opto- and chemogenetic manipulations of mitral/tufted cells (M/TCs) in the OB of non-anesthetized neonatal mice. We show that the neonatal OB synchronizes the limbic circuity in the beta frequency range. Moreover, it drives neuronal and network activity in LEC, as well as subsequently, HP and PFC via long-range projections from mitral cells (MCs) to HP-projecting LEC neurons. Thus, OB activity shapes the communications within limbic circuits during neonatal development.

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bioRxiv2021

Developmental increase of inhibition drives decorrelation of neural activity

Throughout development, the brain transits from early highly synchronous activity patterns to a mature state with sparse and decorrelated neural activity, yet the mechanisms underlying this process are unknown. The developmental transition has important functional consequences, as the latter state allows for more efficient storage, retrieval and processing of information. Here, we show that, in the mouse medial prefrontal cortex (mPFC), neural activity during the first two postnatal weeks decorrelates following specific spatial patterns. This process is accompanied by a concomitant tilting of excitation/inhibition (E-I) ratio towards inhibition. Using optogenetic manipulations and neural network modeling, we show that the two phenomena are mechanistically linked, and that a relative increase of inhibition drives the decorrelation of neural activity. Accordingly, in two mouse models of neurodevelopmental disorders, subtle alterations in E-I ratio are associated with specific impairments in the correlational structure of spike trains. Finally, capitalizing on EEG data from newborn babies, we show that an analogous developmental transition takes place also in the human brain. Thus, changes in E-I ratio control the (de)correlation of neural activity and, by these means, its developmental imbalance might contribute to the pathogenesis of neurodevelopmental disorders.

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bioRxiv2020

Anesthetics uniquely decorrelate hippocampal network activity, alter spine dynamics and affect memory consolidation

General anesthesia is characterized by reversible loss of consciousness accompanied by transient amnesia. Yet, long-term memory impairment is an undesirable side-effect. How different types of general anesthetics (GAs) affect the hippocampus, a brain region central to memory formation and consolidation, is poorly understood. Using extracellular recordings, chronic 2-photon imaging and behavioral analysis, we monitor the effects of isoflurane (Iso), medetomidine/midazolam/fentanyl (MMF), and ketamine/xylazine (Keta/Xyl) on network activity and structural spine dynamics in the hippocampal CA1 area of adult mice. GAs robustly reduced spiking activity, decorrelated cellular ensembles, albeit with distinct activity signatures, and altered spine dynamics. CA1 network activity under all three anesthetics was different to natural sleep. Iso anesthesia most closely resembled unperturbed activity during wakefulness and sleep, and network alterations recovered more readily than with Keta/Xyl and MMF. Correspondingly, memory consolidation was impaired after exposure to Keta/Xyl and MMF, but not Iso. Thus, different anesthetics distinctly alter hippocampal network dynamics, synaptic connectivity, and memory consolidation, with implications for GA strategy appraisal in animal research and clinical settings.

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bioRxiv2020

Bursting mitral cells time the oscillatory coupling between olfactory bulb and entorhinal networks in neonatal mice

Shortly after birth, the olfactory system provides to blind, deaf, non-whisking and motorically-limited rodents not only the main source of environmental inputs, but also the drive boosting the functional entrainment of limbic circuits. However, the cellular substrate of this early communication remains largely unknown. Here we combine in vivo and in vitro patch-clamp and extracellular recordings to reveal the contribution of mitral cell (MC) firing to the early patterns of network activity in the neonatal olfactory bulb (OB) and lateral entorhinal cortex (LEC), the gatekeeper of limbic circuits. We show that MCs predominantly fire either in an irregular bursting or non-bursting pattern during discontinuous theta events in OB. However, the temporal spike-theta phase coupling is stronger for bursting MCs when compared to non-bursting cells. In line with the direct OB projections to LEC, both bursting and non-bursting firing augments during coordinated patterns of entorhinal activity, yet to a higher magnitude for bursting MCs. These cells are stronger temporally coupled to the discontinuous theta events in LEC. Thus, bursting MCs might drive the entrainment of OB-LEC network during neonatal development. KEY POINTSO_LIDuring early postnatal development mitral cells show either irregular bursting or non-bursting firing patterns C_LIO_LIBursting mitral cells preferentially fire during theta bursts in the neonatal OB, being locked to the theta phase C_LIO_LIBursting mitral cells preferentially fire during theta bursts in the neonatal lateral entorhinal cortex and are temporally related to both respiration rhythm- and theta phase C_LIO_LIBursting mitral cells act as cellular substrate of the olfactory drive promoting the oscillatory entrainment of entorhinal networks C_LI

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bioRxiv2020

Knock-down of hippocampal DISC1 in immune-challenged mice impairs the prefrontal-hippocampal coupling and the cognitive performance throughout development

Disrupted-in-Schizophrenia 1 (DISC1) gene represents an intracellular hub of developmental processes and has been related to cognitive dysfunction in psychiatric disorders. Mice with whole-brain DISC1 knock-down show memory and executive deficits as result of impaired prefrontal-hippocampal communication throughout development, especially when combined with early environmental stressors, such as maternal immune activation (MIA). While synaptic dysfunction of layer 2/3 pyramidal neurons in neonatal prefrontal cortex (PFC) has been recently identified as one source of abnormal long-range coupling in these mice, it is still unclear whether the hippocampus (HP) is also compromised during development. Here we aim to fill this knowledge gap by combining in vivo electrophysiology and optogenetics with morphological and behavioral assessment of immune-challenged mice with DISC1 knock-down either in the whole brain (GE) or restricted to pyramidal neurons in CA1 area of intermediate/ventral HP (i/vHP) (GHPE). Both groups of mice show abnormal network activity, sharp-waves (SPWs) and neuronal firing in CA1 area. Moreover, optogenetic stimulation of CA1 pyramidal neurons fails to activate the local circuits in the neonatal PFC. These deficits that persist until pre-juvenile development are due to dendrite sparsification and loss of spines of CA1 pyramidal neurons. As a long-term consequence, DISC1 knock-down in immune-challenged mice leads to poorer recognition memory at pre-juvenile age. Thus, besides PFC, hippocampal CA1 area has a critical role for the developmental miswiring and long-lasting cognitive impairment related to mental illness. Significance StatementDevelopmental miswiring within prefrontal-hippocampal networks has been proposed to account for cognitive impairment in mental disorders. Indeed, during development, long before the emergence of cognitive deficits, the functional coupling within these networks is reduced in mouse models of disease. However, the cellular mechanisms of dysfunction are largely unknown. Here we combine in vivo electrophysiology and optogenetics with behavioral assessment in immune-challenged mice with hippocampus-confined DISC1 knock-down and show that pyramidal neurons in CA1 area are critical for the developmental dysfunction of prefrontal-hippocampal communication and cognitive impairment.

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bioRxiv2020

Gamma activity accelerates during prefrontal development

Gamma oscillations are a prominent activity pattern in the cerebral cortex. While gamma rhythms have been extensively studied in the adult prefrontal cortex in the context of cognitive (dys)functions, little is known about their development. We addressed this issue by using extracellular recordings and optogenetic stimulations in mice across postnatal development. We show that fast rhythmic activity in the prefrontal cortex becomes prominent during the second postnatal week. While initially at about 15 Hz, fast oscillatory activity progressively accelerates with age and stabilizes within gamma frequency range (30-80 Hz) during the fourth postnatal week. Activation of layer 2/3 pyramidal neurons drives fast oscillations throughout development, yet the acceleration of their frequency follows similar temporal dynamics as the maturation of fast-spiking interneurons. These findings uncover the development of prefrontal gamma activity and provide a framework to examine the origin of abnormal gamma activity in neurodevelopmental disorders.

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bioRxiv2020

Early postnatal inhibitory circuit development in the mouse medial prefrontal and primary somatosensory cortex

The prefrontal cortex (PFC) is characterized by protracted maturation. The cellular mechanisms controlling the early development of prefrontal circuits are still largely unknown. Our study delineates the developmental cellular processes in the mouse medial PFC (mPFC) during the second and third postnatal weeks and characterizes their contribution to the changes in network activity. We show that spontaneous inhibitory postsynaptic currents (sIPSC) are increased while spontaneous excitatory postsynaptic currents (sEPSC) are reduced from the second to the third postnatal week. Drug application suggested that the increased sEPSC frequency in mPFC at P10 is due to depolarizing GABAA receptor (GABAAR) function. To further validate this, perforated patch-clamp recordings were obtained and the expression levels of K-Cl co-transporter 2 (KCC2) protein were examined. The reversal potential of IPSCs in response to current stimulation was significantly more depolarized at P10 compared to P20 while KCC2 expression is decreased. Moreover, the number of parvalbumin-expressing GABAergic interneurons increase from P10 to P20 in the mPFC and their intrinsic electrophysiological properties significantly mature. Using computational modeling, we show that the developmental changes in synaptic and intrinsic properties of mPFC neurons contribute to the enhanced network activity in the juvenile compared to neonatal mPFC.

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bioRxiv2019

A Non-negative Measure Of Feature-specific Information Transfer Between Neural Signals

Quantifying both the amount and content of the information transferred between neuronal populations is crucial to understand brain functions. Traditional data-driven methods based on Wiener-Granger causality quantify information transferred between neuronal signals, but do not reveal whether transmission of information refers to one specific feature of external stimuli or another. Here, we developed a new measure called Feature-specific Information Transfer (FIT), that quantifies the amount of information transferred between neuronal signals about specific stimulus features. The FIT quantifies the feature-related information carried by a receiver that was previously carried by a sender, but that was never carried by the receiver earlier. We tested the FIT on simulated data in various scenarios. We found that, unlike previous measures, FIT successfully disambiguated genuine feature-specific communication from non-feature specific communication, from external confounding inputs and synergistic interactions. Moreover, the FIT had enhanced temporal sensitivity that facilitates the estimation of the directionality of transfer and the communication delay between neuronal signals. We validated the FITs ability to track feature-specific information flow using neurophysiological data. In human electroencephalographic data acquired during a face detection task, the FIT demonstrated that information about the eye in face pictures flowed from the hemisphere contralateral to the eye to the ipsilateral one. In multi-unit activity recorded from thalamic nuclei and primary sensory cortices of rats during multimodal stimulation, FIT, unlike Wiener-Granger methods, credibly detected both the direction of information flow and the sensory features about which information was transmitted. In human cortical high-gamma activity recorded with magnetoencephalography during visuomotor mapping, FIT showed that visuomotor-related information flowed from superior parietal to premotor areas. Our work suggests that the FIT measure has the potential to uncover previously hidden feature-specific information transfer in neuronal recordings and to provide a better understanding of brain communication. Author summaryThe emergence of coherent percepts and behavior relies on the processing and flow of information about sensory features, such as the color or shape of an object, across different areas of the brain. To understand how computations within the brain lead to the emergence of these functions, we need to map the flow of information about each specific feature. Traditional methods, such as those based on Wiener-Granger causality, quantify whether information is transmitted from one brain area to another, but do not reveal if the information being transmitted is about a certain feature or another feature. Here, we develop a new mathematical technique for the analysis of brain activity recordings, called Feature-specific Information Transfer (FIT), that can reveal not only if any information is being transmitted across areas, but whether or not such transmitted information is about a certain sensory feature. We validate the method with both simulated and real neuronal data, showing its power in detecting the presence of feature-specific information transmission, as well as the timing and directionality of this transfer. This work provides a tool of high potential significance to map sensory information processing in the brain.

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bioRxiv2018

Identifying neurophysiological features associated with anesthetic state in newborn mice and humans

One Sentence SummaryMachine learning reveals consistent features of anesthetic states assessed by intracranial recordings in newborn mice and multichannel EEG in human neonates and infants.\n\nAbstractMonitoring the hypnotic component of anesthesia during surgeries is critical to prevent intraoperative awareness and reduce adverse side effects. For this purpose, electroencephalographic 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 characterize the effects of different anesthetics on activity of several brain areas in neonatal mice and develop 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 electroencephalographic recordings can be applied to predict anesthetic concentration in neonatal mice, and human neonates and infants. These results might support a novel strategy to monitor anesthetic depth in human newborns.

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bioRxiv2018

Coordinated electrical activity in the olfactory bulb gates the oscillatory entrainment of entorhinal networks in neonatal mice

While the developmental principles of sensory and cognitive processing have been extensively investigated, their synergy has been largely neglected. During early life, most sensory systems are still largely immature. As a notable exception, the olfactory system reaches full maturity during intrauterine life, controlling mother-offspring interactions and neonatal survival. Here, we elucidate the structural and functional principles underlying the communication between olfactory bulb (OB) and lateral entorhinal cortex (LEC) - the gatekeeper of limbic circuitry - during neonatal mouse development. Combining optogenetics, pharmacology, and electrophysiology in vivo with axonal tracing, we show that mitral cell-dependent discontinuous theta bursts in OB drive network oscillations and time the firing in LEC via axonal projections confined to upper cortical layers. Pharmacological silencing of OB activity diminishes entorhinal oscillations. Moreover, odor exposure boosts OB-entorhinal coupling at fast frequencies. Thus, early OB activity shapes the maturation of entorhinal circuits.

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