intrinsic properties

BKCa Channel Contributions to Cerebellar Regulated TSC-Associated Neuropsychiatric Disorders

Project Summary TSC is associated with neurodevelopmental disability including cognitive disability and autism spectrum disorders (ASD) that make up part of TSC associated neuropsychiatric disorders (TAND). The mechanisms for TAND remain poorly understood but studies have increasingly implicated cerebellar dysfunction in the pathogenesis of cognitive and behavioral deficits in both TSC and other neurodevelopmental disorders. A shared feature is cerebellar Purkinje cell (PC) dysfunction. Changes in intrinsic properties of PCs results in both motor and cognitive/ behavioral changes in disease models and in individuals afflicted by these disorders. Mechanistic underpinnings of these altered properties remain unknown, but a significant emerging body of data implicate ion channel dysfunction as the primary etiology of these deficits. The current proposal seeks to delineate the ion channel contribution to PC dysfunction and to TAND-relevant behaviors. In doing so, these studies will produce significant both short- and long-term impact. Short-term: These proposed studies will provide a mechanistic understanding of the contribution of ion channels to the neuronal dysfunction in the cerebellum that has been demonstrated to be causally linked to abnormal TAND-relevant behaviors. In addition, we will target specific ion channels both genetically and pharmacologically to evaluate the benefits of ion channel restoration on both electrophysiological abnormalities but also the TAND-relevant behaviors observed in the model. Long-term: These studies, thus, provide a framework for subsequent clinically-relevant therapeutic development for TAND. First, these studies will uncover the ability for TAND-relevant behaviors to be improved upon targeting ion channel alterations in TSC. These studies will also define molecular targets on which therapeutic development can be targeted, thereby potentially providing a molecular-informed pipeline for therapeutic development. In addition, these studies will utilize clinically-available, FDA-approved pharmacological agents to target ion channel function and investigate the potential therapeutic benefits for these agents for TAND-relevant behaviors. Thus, these studies will address a core gap in knowledge to achieve a better mechanistic understanding of TAND and to develop therapeutic opportunities to address TAND. These studies will not only reveal previously understudied and novel mechanistic underpinnings for these behaviors but will provide pre-clinical insights into the therapeutic utility of clinically-utilized agents for the treatment of TAND-related behaviors, thus potentially providing both immediate and long-term opportunities for the treatment of TAND. Moreover, although these studies focus on TSC, these mechanisms may prove generalizable beyond TSC and provide a shared basis and therapeutic opportunity for other neuropsychiatric/developmental conditions.

Cholinergic modulation of the cerebellum

Many studies have investigated the major glutamatergic inputs to the cerebellum, mossy fibres and climbing fibres, however far less is known about its neuromodulatory inputs. In particular, anatomical studies have described cholinergic input to the cerebellum, yet little is known about its role(s). In this talk, I will present our recent findings which demonstrate that manipulating acetylcholine receptors in the cerebellum causes effects at both a cellular and behavioural level. Activating acetylcholine receptors alters the intrinsic properties and synaptic inputs of cerebellar output neurons, and blocking these receptors results in deficits in a range of behavioural tasks.

Can subjective experience be quantified? Critically examining computational cognitive neuroscience approaches

Computational and cognitive neuroscience techniques have made great strides towards describing the neural computations underlying perceptual inference and decision-making under uncertainty. These tools tell us how and why perceptual illusions occur, which brain areas may represent noisy information in a probabilistic manner, and so on. However, an understanding of the subjective, qualitative aspects of perception remains elusive: qualia, or the personal, intrinsic properties of phenomenal awareness, have remained out of reach of these computational analytic insights. Here, I propose that metacognitive computations, and the subjective feelings that go along with them, give us a solid starting point for understanding subjective experience in general. Specifically, perceptual metacognition possesses ontological and practical properties that provide a powerful and unique opportunity for studying the studying the neural and computational correlates of subjective experience using established tools of computational and cognitive neuroscience. By capitalizing on decades of developments in formal computational model comparisons as applied to the specific properties of perceptual metacognition, we are now in a privileged position to reveal new and exciting insights about how the brain constructs our subjective conscious experiences.

Toward a Comprehensive Classification of Mouse Retinal Ganglion Cells: Morphology, Function, Gene Expression, and Central Projections

I will introduce a web portal for the retinal neuroscience community to explore the catalog of mouse retinal ganglion cell (RGC) types, including data on light responses, correspondences with morphological types in EyeWire, and gene expression data from single-cell transcriptomics. Our current classification includes 43 types, accounting for 90% of the cells in EyeWire. Many of these cell types have new stories to tell, and I will cover two of them that represent opposite ends of the spectrum of levels of analysis in my lab. First, I will introduce the “Bursty Suppressed-by-Contrast” RGC and show how its intrinsic properties rather than its synaptic inputs differentiate its function from that of a different well-known RGC type. Second, I will present the histogram of cell types that project to the Olivary Pretectal Nucleus, focusing on the recently discovered M6 ipRGC.

Traveling UP states in the post-subiculum reveal an anatomical gradient of intrinsic properties

COSYNE 2023

Traveling UP states in the post-subiculum reveal an anatomical gradient of intrinsic properties

The intrinsic properties of somatostatin interneurons in a Mecp2-deficient mouse model of Rett syndrome

FENS Forum 2024