scholarly journals Microglia inhibition rescues developmental hypofrontality in a mouse model of mental illness

2018 ◽  
Author(s):  
Mattia Chini ◽  
Christoph Lindemann ◽  
Jastyn A. Pöpplau ◽  
Xiaxia Xu ◽  
Joachim Ahlbeck ◽  
...  
Keyword(s):  
Mental Illness ◽  
Cognitive Deficits ◽  
Pyramidal Neurons ◽  
List Type ◽  
Spine Density ◽  
Abnormal Rate ◽  
Hippocampal Networks ◽  
Local Circuits ◽  
Circuit Function

SUMMARYCognitive deficits, core features of mental illness, largely result from dysfunction of prefrontal-hippocampal networks. This dysfunction emerges already during early development, before a detectable behavioral readout, yet the cellular elements controlling the abnormal maturation are still unknown. Combining in vivo electrophysiology and optogenetics with neuroanatomy and pharmacology in neonatal mice mimicking the dual genetic - environmental etiology of psychiatric disorders, we identified pyramidal neurons in layer II/III of the prefrontal cortex as key elements causing disorganized oscillatory entrainment of local circuits in beta-gamma frequencies. Their abnormal firing rate and timing result from sparser dendritic arborization and lower spine density. Pharmacological modulation of aberrantly hyper-mature microglia rescues morphological, synaptic and functional neuronal deficits and restores the early circuit function. Elucidation of the cellular substrate of developmental miswiring related to later cognitive deficits opens new perspectives for identification of neurobiological targets, amenable to therapies.HighlightsMice mimicking the etiology of mental illness have dysregulated prefrontal networkStructural and synaptic deficits cause abnormal rate and timing of pyramidal firingWeaker activation of prefrontal circuits results from deficits of pyramidal neuronsRescue of microglial function restores developing prefrontal circuits

scholarly journals Distal axotomy enhances retrograde presynaptic excitability onto injured pyramidal neurons via trans-synaptic signaling

2016 ◽  
Author(s):  
Tharkika Nagendran ◽  
Rylan S. Larsen ◽  
Rebecca L. Bigler ◽  
Shawn B. Frost ◽  
Benjamin D. Philpot ◽  
...  
Keyword(s):  
Dendritic Spines ◽  
Dendritic Spine ◽  
Pyramidal Neurons ◽  
Spine Density ◽  
Axon Injury ◽  
Synaptic Remodeling ◽  
Nerve Tracts ◽  
Specific Increase ◽  
Microfluidic Chambers

AbstractInjury of CNS nerve tracts remodels circuitry through dendritic spine loss and hyper-excitability, thus influencing recovery. Due to the complexity of the CNS, a mechanistic understanding of injury-induced synaptic remodeling remains unclear. Using microfluidic chambers to separate and injure distal axons, we show that axotomy causes retrograde dendritic spine loss at directly injured pyramidal neurons followed by retrograde presynaptic hyper-excitability. These remodeling events require activity at the site of injury, axon-to-soma signaling, and transcription. Similarly, directly injured corticospinal neurons in vivo also exhibit a specific increase in spiking following axon injury. Axotomy-induced hyper-excitability of cultured neurons coincides with elimination of inhibitory inputs onto injured neurons, including those formed onto dendritic spines. Netrin-1 downregulation occurs following axon injury and exogenous netrin-1 applied after injury normalizes spine density, presynaptic excitability, and inhibitory inputs at injured neurons. Our findings show that intrinsic signaling within damaged neurons regulates synaptic remodeling and involves netrin-1 signaling.

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

2020 ◽  
Author(s):  
Xiaxia Xu ◽  
Lingzhen Song ◽  
Ileana L. Hanganu-Opatz
Keyword(s):  
Cognitive Impairment ◽  
Pyramidal Neurons ◽  
Behavioral Assessment ◽  
Network Activity ◽  
Whole Brain ◽  
Knock Down ◽  
Ca1 Pyramidal Neurons ◽  
Ca1 Area ◽  
Local Circuits

AbstractDisrupted-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.

scholarly journals Exercise training improves motor skill learning via selective activation of mTOR

2019 ◽  
Vol 5 (7) ◽  
pp. eaaw1888 ◽  
Author(s):  
Kai Chen ◽  
Yuhan Zheng ◽  
Ji-an Wei ◽  
Huan Ouyang ◽  
Xiaodan Huang ◽  
...  
Keyword(s):  
Exercise Training ◽  
Motor Learning ◽  
Cognitive Deficits ◽  
Molecular Mechanisms ◽  
Pyramidal Neurons ◽  
Ex Vivo ◽  
Mtor Pathway ◽  
Skill Learning ◽  
Mechanistic Target Of Rapamycin

Physical exercise improves learning and memory, but little in vivo evidence has been provided to illustrate the molecular mechanisms. Here, we show that chronic treadmill exercise activates the mechanistic target of rapamycin (mTOR) pathway in mouse motor cortex. Both ex vivo and in vivo recordings suggest that mTOR activation leads to potentiated postsynaptic excitation and enhanced neuronal activity of layer 5 pyramidal neurons after exercise, in association with increased oligodendrogenesis and axonal myelination. Exercise training also increases dendritic spine formation and motor learning. Together, exercise activates mTOR pathway, which is necessary for spinogenesis, neuronal activation, and axonal myelination leading to improved motor learning. This model provides new insights for neural network adaptations through exercises and supports the intervention of cognitive deficits using exercise training.

scholarly journals Knock-Down of Hippocampal DISC1 in Immune-Challenged Mice Impairs the Prefrontal–Hippocampal Coupling and the Cognitive Performance Throughout Development

2020 ◽  
Author(s):  
Xiaxia Xu ◽  
Lingzhen Song ◽  
Ileana L Hanganu-Opatz
Keyword(s):  
Pyramidal Neurons ◽  
Behavioral Assessment ◽  
Neuronal Firing ◽  
Network Activity ◽  
Whole Brain ◽  
Developmental Processes ◽  
Knock Down ◽  
Ca1 Pyramidal Neurons ◽  
Local Circuits

Abstract Disrupted-in-schizophrenia 1 (DISC1) gene represents an intracellular hub of developmental processes. When combined with early environmental stressors, such as maternal immune activation, but not in the absence of thereof, whole-brain DISC1 knock-down leads to memory and executive deficits as result of impaired prefrontal–hippocampal communication throughout development. While synaptic dysfunction in neonatal prefrontal cortex (PFC) has been recently identified as one source of abnormal long-range coupling, the contribution of hippocampus (HP) is still unknown. 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 hippocampal CA1 area (GHPE). We found abnormal network activity, sharp-waves, and neuronal firing in CA1 that complement the deficits in upper layer of PFC. Moreover, optogenetic activating CA1 pyramidal neurons fails to activate the prefrontal local circuits. These deficits that persist till prejuvenile age relate to dendrite sparsification and loss of spines of CA1 pyramidal neurons. As a long-term consequence, DISC1 knock-down in HP leads to poorer recognition memory at prejuvenile age. Thus, DISC1-controlled developmental processes in HP in immune-challenged mice are critical for circuit function and cognitive behavior.

scholarly journals Dysfunction in nonsense-mediated decay, protein homeostasis, mitochondrial function, and brain connectivity in ALS-FUS mice with cognitive deficits

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Wan Yun Ho ◽  
Ira Agrawal ◽  
Sheue-Houy Tyan ◽  
Emma Sanford ◽  
Wei-Tang Chang ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Brain Connectivity ◽  
Expression Patterns ◽  
Long Term Potentiation ◽  
Protein Homeostasis ◽  
Spine Density ◽  
Nonsense Mediated Decay ◽  
Endogenous Expression ◽  
Mitochondrial Functions

AbstractAmyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two ends of the same disease spectrum of adult-onset neurodegenerative diseases that affect the motor and cognitive functions, respectively. Multiple common genetic loci such as fused in sarcoma (FUS) have been identified to play a role in ALS and FTD etiology. Current studies indicate that FUS mutations incur gain-of-toxic functions to drive ALS pathogenesis. However, how the disease-linked mutations of FUS affect cognition remains elusive. Using a mouse model expressing an ALS-linked human FUS mutation (R514G-FUS) that mimics endogenous expression patterns, we found that FUS proteins showed an age-dependent accumulation of FUS proteins despite the downregulation of mouse FUS mRNA by the R514G-FUS protein during aging. Furthermore, these mice developed cognitive deficits accompanied by a reduction in spine density and long-term potentiation (LTP) within the hippocampus. At the physiological expression level, mutant FUS is distributed in the nucleus and cytosol without apparent FUS aggregates or nuclear envelope defects. Unbiased transcriptomic analysis revealed a deregulation of genes that cluster in pathways involved in nonsense-mediated decay, protein homeostasis, and mitochondrial functions. Furthermore, the use of in vivo functional imaging demonstrated widespread reduction in cortical volumes but enhanced functional connectivity between hippocampus, basal ganglia and neocortex in R514G-FUS mice. Hence, our findings suggest that disease-linked mutation in FUS may lead to changes in proteostasis and mitochondrial dysfunction that in turn affect brain structure and connectivity resulting in cognitive deficits.

scholarly journals Alterations of specific inhibitory circuits of the prefrontal cortex underlie abnormal network activity in a mouse model of Down syndrome

2020 ◽  
Author(s):  
Javier Zorrilla de San Martin ◽  
Cristina Donato ◽  
Jérémy Peixoto ◽  
Andrea Aguirre ◽  
Vikash Choudhary ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Prefrontal Cortex ◽  
Cognitive Deficits ◽  
Pyramidal Neurons ◽  
Phase Locking ◽  
Network Activity ◽  
Inhibitory Circuits ◽  
Network Oscillations ◽  
Fast Spiking

AbstractDown syndrome (DS) results in various degrees of cognitive deficits. In DS mouse models, recovery of behavioral and neurophysiological deficits using GABAAR antagonists led to hypothesize an excessive activity of inhibitory circuits in this condition. Nonetheless, whether over-inhibition is present in DS and whether this is due to specific alterations of distinct GABAergic circuits is unknown. In the prefrontal cortex of Ts65Dn mice (a well-established DS model), we found that the dendritic synaptic inhibitory loop formed by somatostatin-positive Martinotti cells (MCs) and pyramidal neurons (PNs) was strongly enhanced, with no alteration of their excitability. Conversely, perisomatic inhibition from parvalbumin-positive (PV) interneurons was unaltered, but PV cells of DS mice lost their classical fast-spiking phenotype and exhibited increased excitability. These microcircuit alterations resulted in reduced pyramidal-neuron firing and increased phase locking to cognitive-relevant network oscillations in vivo. These results define important synaptic and circuit mechanisms underlying of cognitive dysfunctions in DS.

Abstract WP329: The Role of miR-34b/c in Global Ischemic Stroke

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Hyae-Ran Byun ◽  
Morgan Porch ◽  
Fabrizio Pontarelli ◽  
Brenda L Court Vazquez ◽  
R.Suzanne Zukin ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cognitive Deficits ◽  
Neuronal Death ◽  
Target Genes ◽  
Pyramidal Neurons ◽  
Unmet Need ◽  
Global Ischemia ◽  
Hippocampal Ca1

Transient global ischemia arising as a consequence of cardiac arrest in humans causes selective, delayed death of hippocampal CA1 pyramidal neurons and cognitive impairment. Effective treatments to ameliorate the neurodegeneration and cognitive dysfunction associated with global ischemia are an unmet need. Emerging evidence points to a widespread role for microRNAs (miRNAs) as key modulators of target gene expression in neurons. Accordingly, dysregulation of miRNAs are implicated in the pathophysiology of neurodegenerative disease and neurological disorders. Our findings, derived via miRNA-seq, indicate that expression of a subset of microRNAs are altered in postischemic CA1 including miR-34b/c, miR-21, miR-331, miR-181 and miR-29. Ingenuity pathway analysis reveals that miR-34b/c is the leading miR candidate implicated in cell death and survival. A role for miR-34 in the pathogenesis of global ischemia is, as yet, unclear. Here we show ischemia induces p53-dependent activation of miR-34b/c and downregulation of its target genes Bcl-2 and Sirt1, which together promote neuronal death in selectively vulnerable hippocampal CA1 in vivo . Consistent with this, inhibition of miR-34b/c affords neuroprotection, rescues impaired synaptic plasticity and reduces memory deficits in global ischemia. These findings document a causal role for p53-dependent activation of miR-34b/c in neuronal death and identify a novel therapeutic target for amelioration of the neurodegeneration and cognitive deficits associated with ischemic stroke.

scholarly journals Leptin Induces Hippocampal Synaptogenesis via CREB-Regulated MicroRNA-132 Suppression of p250GAP

2014 ◽  
Vol 28 (7) ◽  
pp. 1073-1087 ◽  
Author(s):  
Matasha Dhar ◽  
Mingyan Zhu ◽  
Soren Impey ◽  
Talley J. Lambert ◽  
Tyler Bland ◽  
...  
Keyword(s):  
Emotional Disorders ◽  
Dendritic Spine ◽  
Leptin Receptor ◽  
Pyramidal Neurons ◽  
Camp Response Element Binding ◽  
Spine Density ◽  
Creb Phosphorylation ◽  
Spine Formation ◽  
Hippocampal Synaptogenesis

Leptin acts in the hippocampus to enhance cognition and reduce depression and anxiety. Cognitive and emotional disorders are associated with abnormal hippocampal dendritic spine formation and synaptogenesis. Although leptin has been shown to induce synaptogenesis in the hypothalamus, its effects on hippocampal synaptogenesis and the mechanism(s) involved are not well understood. Here we show that leptin receptors (LepRs) are critical for hippocampal dendritic spine formation in vivo because db/db mice lacking the long form of the leptin receptor (LepRb) have reduced spine density on CA1 and CA3 neurons. Leptin promotes the formation of mature spines and functional glutamate synapses on hippocampal pyramidal neurons in both dissociated and slice cultures. These effects are blocked by short hairpin RNAs specifically targeting the LepRb and are absent in cultures from db/db mice. Activation of the LepR leads to cAMP response element–binding protein (CREB) phosphorylation and initiation of CREB-dependent transcription via the MAPK kinase/Erk pathway. Furthermore, both Mek/Erk and CREB activation are required for leptin-induced synaptogenesis. Leptin also increases expression of microRNA-132 (miR132), a well-known CREB target, which is also required for leptin-induced synaptogenesis. Last, leptin suppresses the expression of p250GAP, a miR132 target, and this suppression is obligatory for leptin's effects as is the downstream target of p250GAP, Rac1. LepRs appear to be critical in vivo as db/db mice have lowered hippocampal miR132 levels and elevated p250GAP expression. In conclusion, we identify a novel signaling pathway by which leptin increases synaptogenesis through inducing CREB transcription and increasing microRNA-mediated suppression of p250GAP activity, thus removing a known inhibitor of Rac1-stimulated synaptogenesis.

scholarly journals Chronic in vivo optogenetic stimulation modulates neuronal excitability, spine morphology and Hebbian plasticity in the mouse hippocampus

2018 ◽  
Author(s):  
Thiago C. Moulin ◽  
Lyvia L. Petiz ◽  
Danielle Rayêe ◽  
Jessica Winne ◽  
Roberto G. Maia ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Ex Vivo ◽  
Morphological Changes ◽  
Spine Density ◽  
Optogenetic Stimulation ◽  
Light Pulses ◽  
Ca1 Region ◽  
Hebbian Plasticity

AbstractProlonged increases in excitation can trigger cell-wide homeostatic responses in neurons, altering membrane channels, promoting morphological changes and ultimately reducing synaptic weights. However, how synaptic downscaling interacts with classical forms of Hebbian plasticity is still unclear. In this study, we investigated whether chronic optogenetic stimulation of hippocampus CA1 pyramidal neurons in freely-moving mice could (a) cause morphological changes reminiscent of homeostatic scaling, (b) modulate synaptic currents that might compensate for chronic excitation, and (c) lead to alterations in Hebbian plasticity. After 24 h of stimulation with 15-ms blue light pulses every 90 s, dendritic spine density and area were reduced in the CA1 region of mice expressing channelrhodopsin-2 (ChR2) when compared to controls. This protocol also reduced the amplitude of mEPSCs for both the AMPA and NMDA components in ex vivo slices obtained from ChR2-expressing mice immediately after the end of stimulation. Lastly, chronic stimulation impaired the induction of LTP and facilitated that of LTD in these slices. Our results indicate that neuronal responses to prolonged network excitation can modulate subsequent Hebbian plasticity in the hippocampus.

scholarly journals Environmental Enrichment Normalizes Hippocampal Timing Coding in a Malformed Hippocampus

2017 ◽  
Author(s):  
Amanda E. Hernan ◽  
J. Matthew Mahoney ◽  
Willie Curry ◽  
Greg Richard ◽  
Marcella M. Lucas ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Spatial Cognition ◽  
Environmental Enrichment ◽  
Pyramidal Neurons ◽  
Spatial Coherence ◽  
Spike Timing ◽  
Cognitive Outcome ◽  
List Type ◽  
Linear Modeling

ABSTRACTNeurodevelopmental insults such as malformations of cortical development (MCD) are a common cause of psychiatric disorders, learning impairments and epilepsy. Animals with MCDs have impairments in spatial cognition that, remarkably, are improved by post-weaning environmental enrichment (EE). To establish the network-level mechanisms responsible for these impacts, hippocampal in vivo single unit recordings were performed in freely moving animals in an open arena. We took a generalized linear modeling approach to extract fine spike timing (FST) characteristics and related these to place cell fidelity used as a surrogate of spatial cognition. We find that MCDs disrupt FST and place-modulated rate coding in hippocampal CA1 and that EE restores both to normal. Moreover, FST parameters predict spatial coherence of neurons, suggesting that mechanisms determining FST are critical for cognition. This suggests that FST parameters could represent a therapeutic target to improve cognition even in the context of a structurally abnormal brain.HIGHLIGHTSEnvironmental enrichment (EE) in rats with cortical malformations improves cognition.EE resolves impaired rate and timing coding of hippocampal pyramidal neurons.Taken together, circuit-level dynamics directly affect quality of the cognitive map.RESEARCH IN CONTEXTInsults during neurodevelopment, particularly those that result in physical malformations in the brain, lead to cognitive impairment, psychiatric disorders and epilepsy. Environmental enrichment (EE) improves cognitive outcome in patients and animal models with brain malformations. Understanding how EE can improve cognition at the level of neural networks can lead to new treatment targets. Remarkably, using an approach that mathematically models neuron firing we show that firing is mistimed in animals with malformations and that EE improves this abnormality. Importantly, timing abnormalities predict abnormalities in cognition at the single neuron level, suggesting that restoring timing could improve learning and memory deficits.

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