Neuromorphic-Based Neuroprostheses for Brain Rewiring: State-of-the-Art and Perspectives in Neuroengineering.

Neuroprostheses are neuroengineering devices that have an interface with the nervous system and supplement or substitute functionality in people with disabilities. In the collective imagination, neuroprostheses are mostly used to restore sensory or motor capabilities, but in recent years, new devices directly acting at the brain level have been proposed. In order to design the next-generation of neuroprosthetic devices for brain repair, we foresee the increasing exploitation of closed-loop systems enabled with neuromorphic elements due to their intrinsic energy efficiency, their capability to perform real-time data processing, and of mimicking neurobiological computation for an improved synergy between the technological and biological counterparts. In this manuscript, after providing definitions of key concepts, we reviewed the first exploitation of a real-time hardware neuromorphic prosthesis to restore the bidirectional communication between two neuronal populations in vitro. Starting from that 'case-study', we provide perspectives on the technological improvements for real-time interfacing and processing of neural signals and their potential usage for novel in vitro and in vivo experimental designs. The development of innovative neuroprosthetics for translational purposes is also presented and discussed. In our understanding, the pursuit of neuromorphic-based closed-loop neuroprostheses may spur the development of novel powerful technologies, such as 'brain-prostheses', capable of rewiring and/or substituting the injured nervous system

Type 3 adenylyl cyclase, neuronal primary cilia, and hippocampus-dependent memory formation

Primary cilia are microtubule-based cellular antennae present in most vertebrate cells including neurons. Neuronal primary cilia have abundant expression of G-protein coupled receptors (GPCRs) and downstream cAMP signaling components such as type 3 adenylyl cyclase (AC3). The deflects of neuronal cilia is associated with many memory-related disorders, such as intellectual disability. Thus far, little is known about how neuronal primary cilia regulate neuronal activity and affect hippocampal memory formation. Episodic memory is thought to be encoded by sparsely distributed memory-eligible neurons in the hippocampus and neocortex. However, it is not clear how memory-eligible neurons interact with one another to form and retrieve a memory. The objectives of my dissertation are to determine the roles of AC3 in regulating cortical protein phosphorylation, to examine the cellular mechanism of episodic memory formation, and to examine how neuronal primary cilia regulate trace fear memory formation. Project 1: Compare protein phosphorylation levels in the prefrontal cortex between AC3 knockout (KO) and wildtype (WT) mice. AC3 represents a key enzyme mediating ciliary cAMP signaling in neurons and is genetically associated with major depressive disorder (MDD) and autism spectrum disorders (ASD). The major downstream effector protein of cAMP in cells is protein kinase A (PKA), whose activation leads to the phosphorylation of numerous proteins to propagate the signaling downstream. In my mass spectrometry-based phosphoproteomic study using conditional AC3 KO mice, I identified thousands of peptides from prefrontal cortical tissues, some of which are differentially phosphorylated in AC3 WT and KO samples. In addition, this effort led to identification of over two hundred proteins, whose phosphorylation were sex-biased. Surprisingly, a high percentage of these targets (31%) are autism-associated proteins/genes. Hence, this study provides the first phosphoproteomic evidence suggesting that sex-biased protein phosphorylation may contribute to the sexual dimorphism of autism. Project 2: Investigate how hippocampal neurons are recruited to interact with each other to encode a trace fear memory. Using in vivo calcium imaging in freely behaving mice, I found that a small portion of highly active hippocampal neurons (termed primed neurons) are actively engaged in memory formation and retrieval. I found that induction of activity synchronization among primed neurons from random dynamics is critical for trace memory formation and retrieval. My work has provided direct in vivo evidence to challenge the long-held paradigm that activation and re-activation of memory cells encodes and retrieves memory, respectively. These findings support a new mechanistic model for associative memory formation, in that primed neurons connect with each other to forge a new circuit, bridging a conditional stimulus with an unconditional stimulus. Project 3: Develop an analytical method to identify primed neurons and determine the roles of neuronal primary cilia on hippocampal neuronal priming and trace memory formation. Neuronal primary cilia are “cellular antennae” which sense and transduce extracellular signals into neuronal soma. However, to date little is known about how neuronal primary cilia influence neuronal functions and hippocampal memory. I utilized conditional Ift88 knockout mice (to ablate cilia) as loss-of-function models. I found that inducible conditional Ift88 KOs display more severe learning deficits compared to their littermate controls. Cilia-ablated mice showed reduced overall neuronal activity, decreased number of primed neurons, and failed to form burst synchronization. These data support the conclusion that alteration of neuronal primary cilia impairs trace fear memory by decreasing hippocampal neuronal priming and the formation of burst synchronization. This study also provides evidence to support the importance of burst synchronization among primed neurons on memory formation and retrieval

Impact of graphene nanosheets on primary astrocytes

Impact of graphene nanosheets on primary astrocyte

Study of neural circuits using multielectrode arrays in movement disorders

Treballs Finals de Grau d'Enginyeria Biomèdica. Facultat de Medicina i Ciències de la Salut. Universitat de Barcelona. Curs: 2022-2023. Tutor/Director: Rodríguez Allué, Manuel JoséNeurodegenerative movement-related disorders are characterized by a progressive degeneration and loss of neurons, which lead to motor control impairment. Although the precise mechanisms underlying these conditions are still unknown, an increasing number of studies point towards the analysis of neural networks and functional connectivity to unravel novel insights. The main objective of this work is to understand cellular mechanisms related to dysregulated motor control symptoms in movement disorders, such as Chorea-Acanthocytosis (ChAc), by employing multielectrode arrays to analyze the electrical activity of neuronal networks in mouse models. We found no notable differences in cell viability between neurons with and without VPS13A knockdown, that is the only gene known to be implicated in the disease, suggesting that the absence of VPS13A in neurons may be partially compensated by other proteins. The MEA setup used to capture the electrical activity from neuron primary cultures is described in detail, pointing out its specific characteristics. At last, we present the alternative backup approach implemented to overcome the challenges faced during the research process and to explore the advanced algorithms for signal processing and analysis. In this report, we present a thorough account of the conception and implementation of our research, outlining the multiple limitations that have been encountered all along the course of the project. We provide a detailed analysis on the project’s economical and technical feasibility, as well as a comprehensive overview of the ethical and legal aspects considered during the execution