Biology subjects

Konopka, G.

Publications and source records attributed to Konopka, G..

28 records · Page 2Linked to original sources

bioRxiv2020

Cell-type and cytosine context-specific evolution of DNA methylation in the human brain

Cell-type specific epigenetic modifications are critical for brain development and neuropsychiatric diseases. Here we elucidate evolutionary origins of neuron- and oligodendrocyte-specific DNA methylation in human prefrontal cortex, and demonstrate dynamic and distinctive changes of CG and CH methylation. We show that the human brain has experienced pronounced reduction of CG methylation during evolution, which significantly contributed to cell-type specific active regulatory regions. On the other hand, a substantial increase of CH methylation occurred during human brain evolution, associated with fine-tuning expression in development and neuronal subtypes. The majority of differential CG methylation between neurons and oligodendrocytes originated before the divergence of hominoids and catarrhine monkeys, and carries strong signal for genetic risk for schizophrenia. Remarkably, a substantial portion of differential CG methylation between neurons and oligodendrocytes emerged in the human lineage and harbors additional genetic risk for schizophrenia, implicating epigenetic evolution of human cortex in increased vulnerability to neuropsychiatric diseases.

genomics↗

bioRxiv2020

An essential role for MEF2C in the cortical response to loss of sleep

Neuronal activity and gene expression in response to the loss of sleep can provide a window into the enigma of sleep function. Sleep loss is associated with brain differential gene expression, an increase in pyramidal cell mEPSC frequency and amplitude, and a characteristic rebound and resolution of slow wave sleep-slow wave activity (SWS-SWA). However, the molecular mechanism(s) mediating the sleep loss response are not well understood. We show that sleep-loss regulates MEF2C phosphorylation, a key mechanism regulating MEF2C transcriptional activity, and that MEF2C function in postnatal excitatory forebrain neurons is required for the biological events in response to sleep loss. These include altered gene expression, the increase and recovery of synaptic strength, and the rebound and resolution of SWS-SWA, which implicate MEF2C as an essential regulator of sleep function. One Sentence SummaryMEF2C is critical to the response to sleep loss.

neuroscience↗

bioRxiv2020

Functional Identification of Specialized Basal Ganglia Circuits that Regulate Vocal Motor Sequences

Disruption of the transcription factor FoxP2, which is enriched in the basal ganglia, impair vocal development in humans and songbirds. The basal ganglia are essential for the selection and sequencing of motor actions, but the circuit mechanisms governing accurate sequencing of learned vocalizations are unknown. Here, we show expression of FoxP2 in the basal ganglia is vital for the fluent initiation and termination of birdsong, and the maintenance of song syllable sequencing in adulthood. Knockdown of FoxP2 imbalances dopamine receptor expression across striatal direct-like and indirect-like pathways, suggesting a role of dopaminergic signaling in regulating vocal-motor sequencing. Confirming this prediction, we show that phasic dopamine activation, and not inhibition, during singing drives repetition of song syllables, thus also impairing fluent initiation and termination of birdsong. These findings demonstrate discrete circuit origins for the dysfluent repetition of vocal elements, a phenotype commonly observed in speech disorders.

neuroscience↗

bioRxiv2020

Autism-linked gene FoxP1 selectively regulates the cultural transmission of learned vocalizations

Autism spectrum disorders (ASD) are characterized by impaired learning of culturally transmitted behaviors like social skills, speech, and language1-3. These behaviors are learned by copying parents and other social models during development, a two-stage process that involves forming memories of appropriate behaviors during social experiences and then using those memories to guide imitation. How ASD-linked genes impair these often-intertwined aspects of learning is not known, thereby limiting our understanding of the developmental progression of ASD and the targeting of therapeutic interventions. Here we show that these aspects of learning are dissociable and that the ASD-linked gene FoxP1 selectively impairs learning from social experience, but not behavioral imitation. Haploinsufficiency of FOXP1 in humans causes FOXP1 syndrome, a neurodevelopmental disorder typified by severe disruptions in speech and language development, and other ASD-associated symptoms4,5. We tested how knockdown of FoxP1 (FP1-KD) affects the cultural transmission of vocal behaviors in zebra finches, a songbird that learns by memorizing and vocally copying the song of an adult song-tutor. We find that FP1-KD blocks song learning in juvenile birds by selectively impairing their ability to encode a memory during social experiences with a songtutor. These learning deficits are linked to disruptions in experience-driven structural and functional plasticity. However, if birds are exposed to tutor-song prior to FP1-KD, their ability to imitate that song during development is unaffected. Thus, FP1-KD impairs cultural transmission of vocalizations by disrupting the ability to form appropriate vocal memories, yet spares the ability to use previously acquired memories to guide vocal learning. This indicates that learning from social experience may be particularly vulnerable in FOXP1 syndrome.

neuroscience↗

bioRxiv2019

The genomic underpinnings of oscillatory biomarkers supporting successful memory encoding in humans

In humans, brain oscillations are thought to support critical features of memory formation such as coordination of activity across regions, consolidation, and temporal ordering of events. However, understanding the molecular mechanisms underlining this activity in humans remains a major challenge. Here, we measured memory-sensitive oscillations using direct intracranial electroencephalography recordings from the temporal cortex of patients performing an episodic memory task. By then employing transcriptomics on the resected tissue from the same patients, we linked gene expression with brain oscillations, identifying genes correlated with oscillatory signatures of memory formation across six frequency bands. A co-expression analysis isolated biomarker-specific modules associated with neuropsychiatric disorders as well as ion channel activity. Using single-nuclei transcriptomic data from this resected tissue, we further revealed that biomarker-specific modules are enriched for both excitatory and inhibitory neurons. This unprecedented dataset of patient-specific brain oscillations coupled to genomics unlocks new insights into the genetic mechanisms that support memory encoding. By linking brain expression of these genes to oscillatory patterns, our data help overcome limitations of phenotypic methods to uncover genetic links to memory performance.

genomics↗

bioRxiv2019

MEF2C hypofunction in neuronal and neuroimmune populations cooperate to produce MEF2C haploinsufficiency syndrome-like behaviors in mice

Microdeletions of the MEF2C gene are linked to a syndromic form of autism termed MEF2C haploinsufficiency syndrome (MCHS). Here, we show that MCHS-associated missense mutations cluster in the conserved DNA binding domain and disrupt MEF2C DNA binding. DNA binding-deficient global Mef2c heterozygous mice (Mef2c-Het) display numerous MCHS-like behaviors, including autism-related behaviors, as well as deficits in cortical excitatory synaptic transmission. We find that hundreds of genes are dysregulated in Mef2c-Het cortex, including significant enrichments of autism risk and excitatory neuron genes. In addition, we observe an enrichment of upregulated microglial genes, but not due to neuroinflammation in the Mef2c-Het cortex. Importantly, conditional Mef2c heterozygosity in forebrain excitatory neurons reproduces a subset of the Mef2c-Het phenotypes, while conditional Mef2c heterozygosity in microglia reproduces social deficits and repetitive behavior. Together our findings suggest that MEF2C regulates typical brain development and function through multiple cell types, including excitatory neuronal and neuroimmune populations.

neuroscience↗

bioRxiv2019

Cortical Foxp2 supports behavioral flexibility and developmental dopamine D1 receptor expression

Genetic studies have associated FOXP2 variation with speech and language disorders and other neurodevelopmental disorders involving pathology of the cortex. In this brain region, FoxP2 is expressed from development into adulthood, but little is known about its downstream molecular and behavioral functions. Here, we characterized cortex-specific Foxp2 conditional knockout mice and found a major deficit in reversal learning, a form of behavioral flexibility. In contrast, they showed normal activity levels, anxiety, and vocalizations, save for a slight decrease in neonatal call loudness. These behavioral phenotypes were accompanied by decreased cortical dopamine D1 receptor (D1R) expression at neonatal and adult stages, while general cortical development remained unaffected. Finally, using single-cell transcriptomics, we identified at least five excitatory and three inhibitory D1R-expressing cell types in neonatal frontal cortex, and we found changes in D1R cell type composition and gene expression upon cortical Foxp2 deletion. Strikingly, these alterations included non-cell-autonomous changes in upper-layer neurons and interneurons. Together these data support a role for Foxp2 in the development of dopamine-modulated cortical circuits and behaviors relevant to neurodevelopmental disorders.

neuroscience↗

bioRxiv2019

Single-cell analysis of Foxp1-driven mechanisms essential for striatal development

The striatum is a critical forebrain structure for integrating cognitive, sensory, and motor information from diverse brain regions into meaningful behavioral output. However, the transcriptional mechanisms that underlie striatal development and organization at single-cell resolution remain unknown. Here, we show that Foxp1, a transcription factor strongly linked to autism and intellectual disability, regulates organizational features of striatal circuitry in a cell-type-dependent fashion. Using single-cell RNA-sequencing, we examine the cellular diversity of the early postnatal striatum and find that cell-type-specific deletion of Foxp1 in striatal projection neurons alters the cellular composition and neurochemical architecture of the striatum. Importantly, using this approach, we identify the non-cell autonomous effects produced by disrupting Foxp1 in one cell-type and the molecular compensation that occurs in other populations. Finally, we identify Foxp1-regulated target genes within distinct cell-types and connect these molecular changes to functional and behavioral deficits relevant to phenotypes described in patients with FOXP1 loss-of-function mutations. These data reveal cell-type-specific transcriptional mechanisms underlying distinct features of striatal circuitry and identify Foxp1 as a key regulator of striatal development.

neuroscience↗

bioRxiv2019

Cell-type specific epigenetic links to schizophrenia risk in brain

The importance of cell-type specific epigenetic variation of non-coding regions in neuropsychiatric disorders is increasingly appreciated, yet data from disease brains are conspicuously lacking. We generated cell-type specific whole-genome methylomes (N=95) and transcriptomes (N=89) from neurons and oligodendrocytes from brains of schizophrenia and matched controls. The methylomes of these two cell-types are highly distinct, with the majority of differential DNA methylation occurring in non-coding regions. DNA methylation difference between control and schizophrenia brains is subtle compared to cell-type difference, yet robust against permuted data and validated in targeted deep-sequencing analyses. Differential DNA methylation between control and schizophrenia tends to occur in cell-type differentially methylated sites, highlighting the significance of cell-type specific epigenetic dysregulation in a complex neuropsychiatric disorder. Our resource provides novel and comprehensive methylome and transcriptome data from distinct cell populations from schizophrenia brains, further revealing reduced cell-type epigenetic distinction in schizophrenia.

genomics↗

bioRxiv2019

Accelerated evolution of oligodendrocytes in human brain

Recent discussions of human brain evolution have largely focused on increased neuron numbers and changes in their connectivity and expression. However, it is increasingly appreciated that oligodendrocytes play important roles in cognitive function and disease. Whether both cell-types follow similar or distinctive evolutionary trajectories is not known. We examined the transcriptomes of neurons and oligodendrocytes in the frontal cortex of humans, chimpanzees, and rhesus macaques. We identified human-specific trajectories of gene expression in neurons and oligodendrocytes and show that both cell-types exhibit human-specific upregulation. Moreover, oligodendrocytes have undergone accelerated gene expression evolution in the human lineage compared to neurons. The signature of acceleration is enriched for cell type-specific expression alterations in schizophrenia. These results underscore the importance of oligodendrocytes in human brain evolution.

evolutionary biology↗