Biology subjects

Kalmbach, B. E.

Publications and source records attributed to Kalmbach, B. E..

4 recordsLinked to original sources

bioRxiv2025

HCN channels reveal conserved and divergent physiology in supragranular pyramidal neurons in primate species

The physiological properties of human and rodent neurons differ, yet the extent to which these differences reflect human specializations is often unclear. Compared with their rodent counterparts, human supragranular pyramidal neurons possess enriched HCN-channel-dependent intrinsic membrane properties and a related sensitivity to synaptic inputs containing delta/theta band frequencies. We tested whether other primate species possess enriched HCN-channel dependent membrane properties. We found ubiquitous HCN1 subunit gene expression in supragranular glutamatergic neurons across New World Monkeys, Old-World Monkeys, and great apes in single nucleus RNA-sequencing datasets. Using Patch-seq recordings from acute and cultured brain slices, we found robust HCN-dependent physiological properties in supragranular pyramidal neurons in a species of New-World monkey (Saimiri sciureus) and two species of Old-World Monkey (Macaca mulatta, Macaca nemestrina). In both human and macaque neocortex, HCN-related intrinsic properties increased in magnitude with increasing laminar depth, especially in one transcriptomic cell type. Within this type, HCN dependent properties were more pronounced in macaque than human neurons. These findings indicate that HCN-governed membrane properties and sensitivity to delta/theta band frequencies are roughly conserved in supragranular pyramidal neurons across at least 36 million years of primate evolution.

neuroscience↗

bioRxiv2023

Integrated multimodal cell atlas of Alzheimer's disease

Alzheimers disease (AD) is the most common cause of dementia in older adults. Neuropathological and imaging studies have demonstrated a progressive and stereotyped accumulation of protein aggregates, but the underlying molecular and cellular mechanisms driving AD progression and vulnerable cell populations affected by disease remain coarsely understood. The current study harnesses single cell and spatial genomics tools and knowledge from the BRAIN Initiative Cell Census Network to understand the impact of disease progression on middle temporal gyrus cell types. We used image-based quantitative neuropathology to place 84 donors spanning the spectrum of AD pathology along a continuous disease pseudoprogression score and multiomic technologies to profile single nuclei from each donor, mapping their transcriptomes, epigenomes, and spatial coordinates to a common cell type reference with unprecedented resolution. Pseudo-progression analysis showed two major epochs corresponding with a slow early increase in pathology and a later exponential increase that correlated with cognitive decline. The early phase included inflammatory microglial and reactive astrocyte component, as well as a selective loss of Sst+ inhibitory neuron types in superficial cortical layers, loss of myelinating oligodendrocytes, and up-regulation of a re-myelination program by OPCs. The later phase involved loss of excitatory neurons and Pvalb and Vip neuron subtypes also predominantly in superficial layers. These cell vulnerabilities were also seen in prefrontal cortex and replicated by other independent studies when integrated with the BRAIN Initiative reference. Study data and exploratory tools are freely available to accelerate progress in AD research at SEA-AD.org.

genomics↗

bioRxiv2022

Impaired dendritic spike generation in the Fragile X prefrontal cortex is due to loss of dendritic sodium channels

Patients with Fragile X syndrome, the leading monogenetic cause of autism, suffer from impairments related to the prefrontal cortex including working memory and attention. Synaptic inputs to the distal dendrites of layer 5 pyramidal neurons in the prefrontal cortex have a weak influence on the somatic membrane potential. To overcome this filtering, distal inputs are transformed into local dendritic Na+ spikes, which propagate to the soma and trigger action potential output. Layer 5 extratelencephalic (ET) PFC neurons project to the brainstem and various thalamic nuclei and are therefore well positioned to integrate task-relevant sensory signals and guide motor actions. We used current clamp and outside-out patch clamp recording to investigate dendritic spike generation in ET neurons from male wild type and Fmr1 knockout (FX) mice. The threshold for dendritic spikes was more depolarized in FX neurons compared to wild type. Analysis of voltage responses to simulated in vivo "noisy" current injections showed that a larger dendritic input stimulus was required to elicit dendritic spikes in FX ET dendrites compared wild type. Patch clamp recordings revealed that the dendritic Na+ conductance was significantly smaller in FX ET dendrites. Taken together, our results suggest that input-output transformation is impaired in ET neurons of the PFC in FX mice. Considering our prior findings that somatic D-type K+ and dendritic HCN-channel function is reduced in ET neurons, we suggest that the integration of information by PFC circuits is fundamentally altered in Fragile X syndrome. KEY POINTSO_LIDendritic spike threshold is depolarized in Layer 5 PFC neurons in FX mice C_LIO_LISimultaneous somatic and dendritic recording with white noise current injections revealed that larger dendritic stimuli were required to elicit dendritic spikes in FX ET neurons C_LIO_LIOutside-out patch clamp recording revealed that dendritic sodium conductance density was lower in FX ET neurons C_LI

neuroscience↗

bioRxiv2020

Evolution of cellular diversity in primary motor cortex of human, marmoset monkey, and mouse

The primary motor cortex (M1) is essential for voluntary fine motor control and is functionally conserved across mammals. Using high-throughput transcriptomic and epigenomic profiling of over 450,000 single nuclei in human, marmoset monkey, and mouse, we demonstrate a broadly conserved cellular makeup of this region, whose similarity mirrors evolutionary distance and is consistent between the transcriptome and epigenome. The core conserved molecular identity of neuronal and non-neuronal types allowed the generation of a cross-species consensus cell type classification and inference of conserved cell type properties across species. Despite overall conservation, many species specializations were apparent, including differences in cell type proportions, gene expression, DNA methylation, and chromatin state. Few cell type marker genes were conserved across species, providing a short list of candidate genes and regulatory mechanisms responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allowed the Patch-seq identification of layer 5 (L5) corticospinal Betz cells in non-human primate and human and characterization of their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell type diversity in M1 across mammals and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations.

neuroscience↗