Biology subjects

Hjerling Leffler, J.

Publications and source records attributed to Hjerling Leffler, J..

5 recordsLinked to original sources

bioRxiv2025

A novel key player in cognitive striatal processes: the Pthlh interneurons

Interneurons in the dorsal striatum provide essential modulatory control over the projecting neurons, known as medium spiny neurons (MSNs), regulating the output of this brain structure, which is critical for motor control, decision-making, and learning. The diversity of interneurons has been recently determined based on single-cell transcriptomic analyses identifying novel populations as the Pthlh-expressing interneurons, one of the most abundant and distinctive inhibitory populations in the human and mouse striatum. Here, we generated a novel Pthlhcre knock-in mouse line that enables comprehensive study of this critical population. Quantitative histological analyses show that this line effectively targets the Pthlh interneuron class, which appears as a stable population across age, sex and the anterior-posterior axis. To elucidate their functional role, we performed selective chemogenetic inhibition of Pthlh interneurons, which caused significant impairments in striatum-dependent cognitive functions and reduced exploratory behaviorur. Importantly, selective silencing did not affect basal locomotion, motor coordination, or anxiety-like behavior. Monosynaptic rabies tracing revealed that Pthlh interneurons receive dense local input from MSN subtypes and diverse long-range afferents from thalamic and different cortical regions. We further confirm that this population displays electrophysiological heterogeneity encompassing fast-spiking and fast-spiking-like phenotypes. Overall, our findings establish Pthlh interneurons as a major inhibitory class essential for cognitive processing--but not gross motor function--acting as key integrators of local MSN feedback and thalamocortical signals. The novel Pthlhcre mouse line provides a valuable resource for future studies of inhibitory diversity in basal ganglia function and related neurological disorders.

neuroscience↗

bioRxiv2019

Transcriptional maintenance of cortical somatostatin interneuron subtype identity during migration

Recent work suggests that cortical interneuron diversity arises from genetic mechanisms guided by the interplay of intrinsic developmental patterning and local extrinsic cues. Individual genetic programs underlying subtype identity are at least partly established in postmitotic neural precursors, prior to their tangential migration and integration in the cortical circuitry. Nevertheless, it is unclear how distinct interneuron identities are maintained during their migration and maturation. Sox6 is a transcription factor with an established role in MGE-derived interneuron maturation and positional identity. To determine its role in maintaining somatostatin (Sst)-expressing interneurons subtype identity, we conditionally removed Sox6 in migrating Sst interneurons and assessed the effects on their mature identity using single-cell RNA-sequencing (scRNAseq), in situ hybridization and electrophysiology. Sox6 removal prior to migration in Sst-expressing neurons reduced subtype diversity without affecting overall number of neurons. Seven out of nine Sst-expressing molecular subtypes were absent in the mature primary somatosensory cortex of Sox6-cKO mice, including the Chodl-Nos1-expressing type which has been shown to be specified at, or shortly after, cell cycle exit. The remaining Sst-expressing subtypes in the Sox6-cKO cortex comprised three molecular subtypes, Crh-C1ql3 and Hpse-Cbln4, and a third subtype that seemed to be a molecular hybrid of these subtypes. Moreover, Sox6-cKO cells still expressed genes enriched within the entire class of Sst-expressing neurons, such as Sst, Lhx6, Satb1, Elfn1 and Mafb. Removal of Sox6 at P7, after cells have reached their final destination and begin integration into the network, did not disrupt Chodl-Nos1 marker expression. Our findings suggest that expression of Sox6 during the migratory phase of cortical interneurons is necessary for maintenance of Sst+ subtype identity, indicating that subtype maintenance during migration requires active transcriptional programs.

neuroscience↗

bioRxiv2019

Transcriptomic correlates of electrophysiological and morphological diversity within and across neuron types

In order to further our understanding of how gene expression contributes to key functional properties of neurons, we combined publicly accessible gene expression, electrophysiology, and morphology measurements to identify cross-cell type correlations between these data modalities. Building on our previous work using a similar approach, we distinguished between correlations which were \"class-driven,\" meaning those that could be explained by differences between excitatory and inhibitory cell classes, and those that reflected graded phenotypic differences within classes. Taking cell class identity into account increased the degree to which our results replicated in an independent dataset as well as their correspondence with known modes of ion channel function based on the literature. We also found a smaller set of genes whose relationships to electrophysiological or morphological properties appear to be specific to either excitatory or inhibitory cell types. Next, using data from Patch-seq experiments, allowing simultaneous single-cell characterization of gene expression and electrophysiology, we found that some of the gene-property correlations observed across cell types were further predictive of within-cell type heterogeneity. In summary, we have identified a number of relationships between gene expression, electrophysiology, and morphology that provide testable hypotheses for future studies.

neuroscience↗

bioRxiv2018

Molecular architecture of the mouse nervous system

The mammalian nervous system executes complex behaviors controlled by specialised, precisely positioned and interacting cell types. Here, we used RNA sequencing of half a million single cells to create a detailed census of cell types in the mouse nervous system. We mapped cell types spatially and derived a hierarchical, data-driven taxonomy. Neurons were the most diverse, and were grouped by developmental anatomical units, and by the expression of neurotransmitters and neuropeptides. Neuronal diversity was driven by genes encoding cell identity, synaptic connectivity, neurotransmission and membrane conductance. We discovered several distinct, regionally restricted, astrocytes types, which obeyed developmental boundaries and correlated with the spatial distribution of key glutamate and glycine neurotransmitters. In contrast, oligodendrocytes showed a loss of regional identity, followed by a secondary diversification. The resource presented here lays a solid foundation for understanding the molecular architecture of the mammalian nervous system, and enables genetic manipulation of specific cell types.

neuroscience↗

bioRxiv2017

Functional consequences of genetic loci associated with intelligence in a meta-analysis of 87,740 individuals

Variance in IQ is associated with a wide range of health outcomes, and 1% of the population are affected by intellectual disability. Despite a century of research, the fundamental neural underpinnings of intelligence remain unclear. We integrate results from genome-wide association studies (GWAS) of intelligence with brain tissue and single cell gene expression data to identify tissues and cell types associated with intelligence. GWAS data for IQ (N = 78,308) were meta-analyzed with an extreme-trait cohort of 1,247 individuals with mean IQ [~]170 and 8,185 controls. Genes associated with intelligence implicate pyramidal neurons of the somatosensory cortex and CA1 region of the hippocampus, and midbrain embryonic GABAergic neurons. Tissue-specific analyses find the most significant enrichment for frontal cortex brain expressed genes. These results suggest specific neuronal cell types and genes may be involved in intelligence and provide new hypotheses for neuroscience experiments using model systems.

genomics↗