Biology subjects

Holthoff, K.

Publications and source records attributed to Holthoff, K..

8 recordsLinked to original sources

bioRxiv2026

Spontaneous network activity links misrouted interneuron migration to cortical maturation abnormalities

Cortical inhibitory neurons (CIN) populate the neocortex and hippocampus by extensive tangential migration. This process is highly vulnerable to genetic and environmental disturbances and is linked to neuropsychiatric disorders. However, the mechanisms by which transient migratory abnormalities translate into persistent functional deficits remain poorly understood. Here, we utilized a conditional Cxcr4 knockout to investigate the consequences of disrupted migratory guidance - a feature of genetic schizophrenia models. This demonstrated that despite migrating in ectopic cortical layers, CIN quantitatively colonized the neocortex until birth, whereas limbic regions developed a permanent deficit in CIN numbers. Furthermore, CIN failed to populate the neocortical marginal zone, a transient reservoir for late-born CIN destined for superficial cortical layers. Consequently, the layering and molecular identities of CIN, as well as the synaptic connectivity and spontaneous activity of the neuronal network, were significantly altered in the early postnatal neocortex. Although abnormal CIN layering was gradually compensated before maturity, functional differences persisted, as evidenced by facilitated propagation of sensory stimuli between cortical areas. These results demonstrate that CIN migration is an instructive process critical for activity-driven early postnatal network maturation and CIN identity, thus providing a mechanistic link between migratory guidance and the integrity of mature circuits.

neuroscience↗

bioRxiv2025

The chloride cotransporter NKCC1 regulates self-renewal of hippocampal neural stem cells via the transcription factor Sox11

The GABAergic-mediated depolarization plays a key role in controlling stem cell fate and neurogenesis within the dentate gyrus of the hippocampal formation. This depolarization effect is highly dependent on the balance between the chloride co-transporters NKCC1 and KCC2. It is not known how changes in NKCC1 modulate the fate of Nestin-positive stem cells (NSCs) in the hippocampus during adult neurogenesis. In our study, we demonstrate that a knockout of Nkcc1 in NSCs increase their proliferation by symmetric self-renewal and expand the stem cell pool. Using single-cell RNA sequencing, we identified Sox11 as a key transcription factor that is significantly downregulated following Nkcc1 knockout. In agreement with this finding, we found that Sox11 knockout enhances proliferation and self-renewal of NSCs, which is also marked by an increase in symmetric stem cell division. Based on these findings, we propose that altering Nkcc1 expression in NSCs shifts their fate from neurogenesis towards self-renewal via Sox11 regulation. Furthermore, we observed that NKCC1 levels decline in NSCs during aging, which correlates with a further increase in self-renewal. Our data strongly suggest that the age-related decline in NKCC1 levels promote symmetric division and self-renewal contributing to the age-dependent decrease in neurogenesis. NKCC1 via Sox11 is a key regulator of NSCs fate decision, critically balancing self-renewal and neuronal differentiation in the adult hippocampus. HighlightsNKCC1 is a key factor in regulating the Nestin-positive neural stem cell symmetric self-renewal. Sox11 is a downstream effector of NKCC1 in Nestin-positive stem cells and is involved in expansion of the stem cell pool. Aging reduces NKCC1 expression in Nestin-positive stem cells and increases their self-renewal. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=170 HEIGHT=200 SRC="FIGDIR/small/662334v1_ufig1.gif" ALT="Figure 1000"> View larger version (38K): org.highwire.dtl.DTLVardef@1babdcforg.highwire.dtl.DTLVardef@1038bfborg.highwire.dtl.DTLVardef@1db105corg.highwire.dtl.DTLVardef@10f2cde_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Anti-NMDAR encephalitis alters intrinsic spatiotemporal coding by enhancing neuronal coupling and clustering

Autoimmune anti-NMDA-receptor encephalitis is characterized by severe neuropsychiatric symptoms including memory dysfunction and seizures. However, it remains enigmatic what functional changes at the multi-neuronal level mediate network dysfunction. We used two-photon in vivo recording in a passive-transfer mouse model with patients monoclonal anti-GluN1-autoantibodies during slow-wave sleep-like conditions, a critical phase for memory processing. We find enhanced functional coupling and clustering between hippocampal CA1 pyramidal neurons (PNs), which intrinsically expose the network to hypersynchrony. These connectivity changes are associated with a selective preservation of strong excitatory synapses despite overall reduced excitation, thus enhancing hub-like properties of functionally connected PNs. Furthermore, we find abnormal PN firing characteristics, decreased transmission failure, and increased similarity of spontaneous spatiotemporal activity patterns, all affecting CA1 intrinsic neuronal coding. Collectively, the functional rewiring of hippocampal networks and altered intrinsic information processing provide new mechanistic insights into the NMDAR-hypofunction consequences and pathomechanisms of anti-NMDAR encephalitis symptomatology.

neuroscience↗

bioRxiv2024

Harnessing early multimodal motor training to drive motor recovery and brain-wide structural reorganization after stroke

Stroke survivors often suffer from severe motor impairments, highlighting the critical need for effective rehabilitation strategies. In experimental models, extensive task-specific motor training within the first few weeks post-stroke significantly mitigates motor deficits. However, whether more multimodal motor training approaches after stroke can restore task-specific performance in non-trained motor tasks remains largely unknown. Additionally, while stroke itself triggers structural brain reorganization, the influence of early multimodal motor training on this process remains unclear. Here, we employed T2-weighted MRI to investigate brain region-specific volumetric changes over eight weeks in rats subjected to stroke and subsequent early multimodal motor training. We found that this combination not only facilitated task-specific motor function recovery, but also induced dramatic, multi-region, brain-wide volumetric changes. Specifically, over 80 locations within 50 distinct brain regions across both hemispheres exhibited substantial volumetric alterations in a predominantly bilateral symmetric pattern. In contrast, stroke or training alone resulted in changes in 8-15 locations within 7-13 brain regions, with stroke alone primarily affecting the infarcted hemisphere. Analysis of temporal volume changes revealed two distinct trajectories in post-stroke trained rats: one of initial swelling followed by shrinkage, and another of initial shrinkage followed by swelling, suggesting an early and delayed motor learning period. Overall, our findings demonstrate that multimodal motor training early after stroke effectively restores task-specific motor function and profoundly reshapes brain structure on a brain-wide scale, offering vital insights for developing optimized rehabilitation protocols to maximize recovery in stroke patients.

neuroscience↗

bioRxiv2024

Chemogenetic silencing reveals presynaptic Gi/o protein-mediated inhibition of synchronized activity in the developing hippocampus in vivo

The development of neuronal circuits is an activity-dependent process. Research aimed at deciphering the learning rules governing these developmental refinements is increasingly utilizing a class of chemogenetic tools that employ Gi/o protein signaling (Gi-DREADDs) for neuronal silencing. However, their mechanisms of action and inhibitory efficacy in immature neurons with incompletely developed Gi/o signaling are poorly understood. Here, we analyze the impact of Gi/o signaling on cellular and network excitability in the neonatal hippocampus by expressing the Gi-DREADD hM4Di in telencephalic glutamatergic neurons of neonatal mice of both sexes. Using acousto-optic two-photon Ca2+ imaging, we report that activation of hM4Di leads to a complete arrest of spontaneous synchronized activity in CA1 in vitro. Electrophysiological analyses demonstrate that hM4Di-mediated silencing is not accounted for by changes in intrinsic excitability of CA1 pyramidal cells (PCs). Instead, activation of hM4Di robustly restrains synaptic glutamate release by the first postnatal week, effectively reducing recurrent excitation in CA1. In vivo, inhibition through hM4Di potently suppresses early sharp waves (eSPWs) and discontinuous oscillatory network activity in CA1 of head-fixed mice before eye opening. In summary, hM4Di dampens glutamatergic neurotransmission through a presynaptic mechanism sufficient to terminate spontaneous synchronized activity in the neonatal CA1. Our findings have implications for designing and interpreting experiments utilizing Gi-DREADDs in immature neurons and further point to a potential role of Gi/o-dependent endogenous neuromodulators in activity-dependent hippocampal development. Significance StatementRecent advances in understanding how early activity shapes developing brain circuits increasingly rely on Gi/o-dependent inhibitory chemogenetic tools (Gi-DREADDs). However, their single-cellular mechanisms and efficacy in neurons with immature Gi/o signaling are elusive. To close this gap, we analyzed the impact of the Gi-DREADD hM4Di in the neonatal murine hippocampus. We report that hM4Di does not mediate hyperpolarization or shunting but rather acts as a potent presynaptic silencer of glutamatergic neurotransmission in CA1 pyramidal cells. Presynaptic inhibition of excitation suffices to arrest spontaneous synchronized network activity in vitro and in vivo. Our findings provide novel insights into the generative mechanisms of spontaneous synchronized activity and bear relevance for applying chemogenetic silencing at early stages of brain development.

neuroscience↗

bioRxiv2022

A primary sensory cortical interareal feedforward inhibitory circuit for tacto-visual integration

Tactile sensation and vision are often both utilized for the exploration of objects that are within reach though it is not known whether or how these two distinct sensory systems might combine such information. Here in mice we find that stimulation of the contralateral whisker array suppresses visually evoked activity in a subarea of primary visual cortex (VISp) whose visual space covers the whisker search space. This is mediated by local fast spiking interneurons that receive a direct cortico-cortical input predominantly from layer 6 of the primary somatosensory barrel cortex (SSp-bfd). These data demonstrate functional convergence within and between two primary sensory cortical areas for multisensory object detection and recognition.

neuroscience↗

bioRxiv2021

Network instability dynamics drive a transient bursting period in the developing hippocampus in vivo

Spontaneous correlated activity is a universal hallmark of immature neural circuits. However, the cellular dynamics and intrinsic mechanisms underlying network burstiness in the intact developing brain are largely unknown. Here, we use two-photon Ca2+ imaging to comprehensively map the developmental trajectories of spontaneous network activity in hippocampal area CA1 in vivo. We unexpectedly find that network burstiness peaks after the developmental emergence of effective synaptic inhibition in the second postnatal week. We demonstrate that the enhanced network burstiness reflects an increased functional coupling of individual neurons to local population activity. However, pairwise neuronal correlations are low, and network bursts (NBs) recruit CA1 pyramidal cells in a virtually random manner. Using a dynamic systems modeling approach, we reconcile these experimental findings and identify network bi-stability as a potential regime underlying network burstiness at this age. Our analyses reveal an important role of synaptic input characteristics and network instability dynamics for NB generation. Collectively, our data suggest a mechanism, whereby developing CA1 performs extensive input-discrimination learning prior to the onset of environmental exploration.

neuroscience↗

bioRxiv2020

Intraneuronal chloride accumulation via NKCC1 is not essential for hippocampal network development in vivo

NKCC1 is the primary transporter mediating chloride uptake in immature principal neurons, but its role in the development of in vivo network dynamics and cognitive abilities remains unknown. Here, we address the function of NKCC1 in developing mice using electrophysiological, optical and behavioral approaches. We report that NKCC1 deletion from telencephalic glutamatergic neurons decreases in-vitro excitatory GABA actions and impairs neuronal synchrony in neonatal hippocampal brain slices. In vivo, it has a minor impact on correlated spontaneous activity in the hippocampus and does not affect network activity in the intact visual cortex. Moreover, long-term effects of the developmental NKCC1 deletion on synaptic maturation, network dynamics and behavioral performance are subtle. Our data reveal a neural network function of depolarizing GABA in the hippocampus in vivo, but challenge the hypothesis that NKCC1 is essential for major aspects of hippocampal development.

neuroscience↗