Biology subjects

Kasten, M. R.

Publications and source records attributed to Kasten, M. R..

5 recordsLinked to original sources

bioRxiv2026

Parvalbumin interneurons and dentate gyrus homeostatic dysregulation shape epileptogenesis in Angelman syndrome model mice

Understanding how neural circuits transition from seizure-resistant to seizure-prone is essential for developing improved epilepsy therapies. Here, we study this process by leveraging the heightened susceptibility to seizure kindling of Angelman syndrome (AS) model mice, which lack the maternal Ube3a (mUbe3a) allele. We identify parvalbumin-expressing (PV+) interneurons as critical gatekeepers; selective mUbe3a deletion in PV+ neurons phenocopies enhanced AS epileptogenesis, whereas restoring UBE3A broadly in GABAergic neurons confers seizure resistance. Further, pathological remodeling of the extracellular matrix in the dentate gyrus faithfully tracks with post-kindling seizure susceptibility, highlighting this region's particular relevance to enhanced epileptogenesis. Mechanistically, we uncover a 'two-hit' electrophysiologic phenomenon in AS model mice: kindling fails to recruit compensatory inhibition onto dentate granule cells and instead drives their maladaptive intrinsic hyperexcitability. Together, these findings link cell type-specific inhibitory dysfunction and altered homeostatic plasticity to epileptogenesis, suggesting future circuit-based treatment strategies.

neuroscience↗

bioRxiv2026

Ascending inputs to inferior colliculus subdivisions reveal pathway-specific hybrid organization in the external cortex

The inferior colliculus (IC) is a major hub of the auditory system, integrating ascending inputs from auditory and non-auditory brainstem nuclei before relaying information to the thalamus, and ultimately, the cortex. The IC is classically divided into the central nucleus (CIC) and surrounding shell regions, including the external (ECIC) and dorsal (DCIC) cortices. Although numerous tracing studies have described ascending inputs to the IC, most have either treated the IC as a uniform structure or distinguished only core and shell regions, leaving potential heterogeneity within the shell unresolved. Here, we performed retrograde tracing from distinct subdivisions of the mouse IC to compare their ascending input organization. By systematically targeting the CIC, DCIC, and both rostral and caudal ECIC and registering labeled neurons to a standardized brain atlas, we quantified input neurons across auditory and non-auditory brainstem structures. The CIC exhibited input patterns largely consistent with canonical pathways. In contrast, the DCIC received greater input from paralemniscal, periolivary, and non-auditory nuclei. Notably, the ECIC did not simply receive DCIC-like inputs or occupy an intermediate position between CIC and DCIC. Instead, it displayed a pathway-specific hybrid organization: inputs from the nuclei of the lateral lemniscus and superior olivary complex were largely CIC-like, whereas inputs from the cochlear nucleus and non-auditory regions resembled those of the DCIC. Furthermore, rostral and caudal ECIC showed overlapping but distinct input patterns. Together, these results reveal heterogeneous ascending connectivity across IC subdivisions and identify the ECIC as a hybrid interface that bridges CIC-like and DCIC-like ascending pathways. Significance StatementThe inferior colliculus is often divided into a lemniscal core and nonlemniscal shell, but whether shell subdivisions share a common ascending input organization has not been directly tested. By systematically mapping ascending inputs to the central nucleus, dorsal cortex, and rostral and caudal external cortex, we show that the shell regions are not uniform. Instead, the external cortex combines core-like inputs from the nuclei of the lateral lemniscus and the superior olivary complex with dorsal cortex-like inputs from the cochlear nucleus and non-auditory regions. These findings revise the classical core-versus-shell framework and provide an anatomical basis for parallel midbrain pathways, in which the external cortex is positioned for fast auditory signaling while simultaneously receiving contextual and multisensory modulation.

neuroscience↗

bioRxiv2025

Fusiform Cells in the Dorsal Cochlear Nucleus Change Intrinsic Electrophysiological Properties and Morphologically Remodel Their Basal Dendrites with Age

Age-related hearing loss (ARHL) is the most common cause of sensorineural hearing loss. The cochlear nucleus, the first central auditory structure to receive input from the cochlea, has been shown to be disrupted by ARHL. Fusiform cells (FC), the principal output cell of the dorsal part of the cochlear nucleus (DCN), mature physiologically during hearing onset. Specifically, FCs increase in rate of action potential (AP) rise and decay, stabilizing by postnatal day 14 (P14) in mice. However, whether FC intrinsic electrophysiological properties and morphological characteristics continue to change throughout the life of mice, and how they change due to ARHL, is unknown. We characterized electrophysiological and morphological properties of FCs from CBA/CaJ mice at five stages of age: preweaning (P15-20), pubescent (P21-49), young adult (P50-179), mature adult (P180-364), and old adult (P550-578). Our old adult mice had smaller auditory brainstem evoked response amplitudes and loss of some hair cells, indicative of ARHL onset. We observed no change in FC membrane properties with age. FCs from the old adult group had elevated firing rates, faster repolarization rates, and shorter AP half-widths. Morphologically, there was no change in FC soma shape or size. However, a significant decrease in basal dendritic arborization occurred between preweaning and pubescent ages, followed by an increase in our old adult group, suggesting age-dependent remodeling of the basal dendritic tree at the onset of ARHL. Together, these results suggest that FC physiology and morphology are relatively stable post weaning and become altered during the onset of ARHL. NEW & NOTEWORTHYEx vivo patch-clamp recordings within the DCN are traditionally performed using young mice, rarely exceeding weaning age. Here, we were able to successfully record FCs from mice that were 15 days old up to 578 days old. We observed changes in FC firing properties, AP half-width, repolarization rate, and basal dendritic complexity in our old adult group, suggesting possible compensation for the development of age-related hearing loss.

neuroscience↗

bioRxiv2022

Tauopathy and alcohol consumption interact to alter locus coeruleus excitatory transmission and excitability in male and female mice

Alcohol use disorder is a major public health concern in the United States. Recent work has suggested a link between chronic alcohol consumption and the development of tauopathy disorders, such as Alzheimers Disease and Frontal-Temporal Dementia. However, relatively little work has investigated changes in neural circuitry involved in both tauopathy disorders and alcohol use disorder. The locus coeruleus (LC) is the major noradrenergic nuclei in the brain and is one of the earliest sites to be affected by tau lesions. The LC is also implicated in the rewarding effects of ethanol and alcohol withdrawal. In this study we assessed effects of long-term ethanol consumption and tauopathy on the physiology of LC neurons. Male and female P301S mice, a humanized transgenic mouse model of tauopathy, underwent 16 weeks of intermittent access to 20% ethanol from 3 to 7 months of age. We observed higher total alcohol consumption in female mice regardless of genotype. Male P301S mice consumed more ethanol and had a greater preference for ethanol than WT males. At the end of the drinking study, LC function was assessed using ex vivo whole cell electrophysiology. We found significant changes in excitatory inputs to the LC due to both ethanol and genotype., We found significantly increased excitability of the LC due to ethanol with greater effects in female P301S mice than WT. Our study identifies significant changes in the LC due to interactions between tauopathy and long-term ethanol use. These findings could have important implications regarding LC activity and changes in behavior due to both ethanol and tauopathy related dementia.

neuroscience↗

bioRxiv2019

Classification of Neurons in the Adult Mouse Cochlear Nucleus: Linear Discriminant Analysis

The cochlear nucleus (CN) transforms the spike trains of spiral ganglion cells into a new set of sensory representations that are essential for auditory discriminations and perception. These transformations require the coordinated activity of different classes of neurons that are embryologically derived from distinct sets of precursors. Decades of investigation have shown that the neurons of the CN are differentiated by their ion channel expression and intrinsic excitability. In the present study we have used linear discriminant analysis (LDA) to perform an unbiased analysis of measures of the responses of CN neurons to current injections to mathematically separate cells on the basis of both morphology and physiology. Recordings were made from cells in brain slices from CBA mice and a transgenic mouse line, NF107, crossed against the Ai32 line. For each cell, responses to current injections were analyzed for spike rate, spike shape (action potential height, afterhyperpolarization depth, first spike half-width), input resistance, resting membrane potential, membrane time constant, hyperpolarization-activated sag and time constant. Cells were filled with dye for morphological classification, and visually classified according to published accounts. The different morphological classes of cells were separated with the LDA. Ventral cochlear nucleus (VCN) bushy cells, planar multipolar (T-stellate) cells, and radiate multipolar (D-stellate) cells were in separate clusters, and were also separated from all of the neurons from the dorsal cochlear nucleus (DCN). Within the DCN, the pyramidal cells and tuberculoventral cells were largely separated from a distinct clusters of cartwheel cells. DCN cells fell largely within a plane in the first 3 principal axes, whereas VCN cells were in 3 clouds approximately orthogonal to this plane. VCN neurons from the two mouse strains were slightly separated, indicating either a strain dependence or the differences in slice preparation methods. We conclude that cochlear nucleus neurons can be objectively distinguished based on their intrinsic electrical properties, but that such distinctions are still best aided by morphological identification.

neuroscience↗