Biology subjects

Manis, P. B.

Publications and source records attributed to Manis, P. B..

7 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↗

bioRxiv2025

Noncanonical Short-Latency Auditory Pathway Directly Activates Deep Cortical Layers

Auditory processing in the cerebral cortex is considered to begin with thalamocortical inputs to layer 4 (L4) of the primary auditory cortex (A1). In this canonical model, A1 L4 inputs initiate a hierarchical cascade, with higher-order cortices receiving pre-processed information for the slower integration of complex sounds. Here, we identify alternative ascending pathways in mice that bypass A1 and directly reach multiple layers of the secondary auditory cortex (A2), indicating parallel activation of these areas alongside sequential information processing. We found that L6 of both A1 and A2 receive short-latency (<10 ms) sound inputs, comparable in speed to the canonical A1 L4 input but transmitted through higher-order thalamic nuclei. Additionally, A2 L4 is innervated by a caudal subdivision within the traditionally defined primary thalamus, which we now identify as belonging to the non-primary system. Notably, both thalamic regions receive projections from distinct subdivisions of the higher-order inferior colliculus, which in turn are directly innervated by cochlear nucleus neurons. These findings reveal alternative ascending pathways reaching A2 at L4 and L6 via secondary subcortical structures. Thus, higher-order auditory cortex processes both slow, pre-processed information and rapid, direct sensory inputs, enabling parallel and distributed processing of fast sensory information across cortical areas.

neuroscience↗

bioRxiv2022

Two Synaptic Convergence Motifs Define Functional Roles for Inputs to Cochlear Nucleus Bushy Cells

Globular bushy cells (GBCs) of the cochlear nucleus play central roles in the temporal processing of sound. Despite investigation over many decades, fundamental questions remain about their dendrite structure, afferent innervation, and integration of synaptic inputs. Here, we use volume electron microscopy (EM) to construct synaptic maps that precisely specify convergence ratios and synaptic weights for auditory- nerve innervation and accurate surface areas of all postsynaptic compartments. Detailed biophysically-based compartmental models can help develop hypotheses regarding how GBCs integrate inputs to yield their recorded responses to sound. We established a pipeline to export a precise reconstruction of auditory nerve axons and their endbulb terminals together with high-resolution dendrite, soma, and axon reconstructions into biophysically-detailed compartmental models that could be activated by a standard cochlear transduction model. With these constraints, the models predict auditory nerve input profiles whereby all endbulbs onto a GBC are subthreshold (coincidence detection mode), or one or two inputs are suprathreshold (mixed mode). The models also predict the relative importance of dendrite geometry, soma size, and axon initial segment length in setting action potential threshold and generating heterogeneity in sound-evoked responses, and thereby propose mechanisms by which GBCs may homeostatically adjust their excitability. Volume EM also reveals new dendritic structures and dendrites that lack innervation. This framework defines a pathway from subcellular morphology to synaptic connectivity, and facilitates investigation into the roles of specific cellular features in sound encoding. We also clarify the need for new experimental measurements to provide missing cellular parameters, and predict responses to sound for further in vivo studies, thereby serving as a template for investigation of other neuron classes.

neuroscience↗

bioRxiv2019

Muscarinic modulation of spike-timing dependent plasticity at recurrent layer 2/3 synapses in mouse auditory cortex

Cholinergic systems contribute to the refinement of auditory cortical receptive fields by activating muscarinic acetylcholine receptors (mAChRs). However, the specific cellular and synaptic mechanisms underlying acetylcholines effects on cortical circuits are not fully understood. In this study, we investigate the effects of muscarinic receptor modulation on spike-timing dependent plasticity (STDP) at synapses onto layer 2/3 pyramidal neurons in mouse auditory cortex (AC). Synapses onto layer 2/3 pyramidal neurons exhibit a STDP rule for pairing of postsynaptic spike bursts with single presynaptic stimuli. Pre-before-post pairing at +10 ms results in a timing-dependent long-term potentiation (tLTP), whereas pre-before-post pairing at +50 ms intervals, and post-before-pre pairing at -10 to -20 ms produce a timing-dependent long-term depression. We also characterize how mAChR activation affects plasticity at these synapses, focusing on the induction of tLTP. During pre-before-post pairing at +10 ms, mAChR activation by either carbachol or oxotremorine-M suppresses tLTP. mAChR activation also reduces the NMDA-receptor dependent synaptically evoked increase in calcium in dendrites, apparently without affecting presynaptic transmitter release. Pharmacological experiments suggest that M1 and M3 receptors are not involved in the mAChR-mediated suppression of tLTP. Taken together, these results suggest activating mAChRs in layer 2/3 intracortical circuits can modify the circuit dynamics of AC by depressing tLTP mediated by NMDA receptors, and depressing calcium influx at excitatory synapses onto layer 2/3 pyramidal cells.

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↗