The Missing Piece? A Case for Microglia's Prominent Role in the Therapeutic Action of Anesthetics, Ketamine, and Psychedelics.

There is much excitement surrounding recent research of promising, mechanistically novel psychotherapeutics - psychedelic, anesthetic, and dissociative agents - as they have demonstrated surprising efficacy in treating central nervous system (CNS) disorders, such as mood disorders and addiction. However, the mechanisms by which these drugs provide such profound psychological benefits are still to be fully elucidated. Microglia, the CNS's resident innate immune cells, are emerging as a cellular target for psychiatric disorders because of their critical role in regulating neuroplasticity and the inflammatory environment of the brain. The following paper is a review of recent literature surrounding these neuropharmacological therapies and their demonstrated or hypothesized interactions with microglia. Through investigating the mechanism of action of psychedelics, such as psilocybin and lysergic acid diethylamide, ketamine, and propofol, we demonstrate a largely under-investigated role for microglia in much of the emerging research surrounding these pharmacological agents. Among others, we detail sigma-1 receptors, serotonergic and γ-aminobutyric acid signalling, and tryptophan metabolism as pathways through which these agents modulate microglial phagocytic activity and inflammatory mediator release, inducing their therapeutic effects. The current review includes a discussion on future directions in the field of microglial pharmacology and covers bidirectional implications of microglia and these novel pharmacological agents in aging and age-related disease, glial cell heterogeneity, and state-of-the-art methodologies in microglial research.

The implication of a diversity of non-neuronal cells in disorders affecting brain networks.

In the central nervous system (CNS) neurons are classically considered the functional unit of the brain. Analysis of the physical connections and co-activation of neurons, referred to as structural and functional connectivity, respectively, is a metric used to understand their interplay at a higher level. A myriad of glial cell types throughout the brain composed of microglia, astrocytes and oligodendrocytes are key players in the maintenance and regulation of neuronal network dynamics. Microglia are the central immune cells of the CNS, able to affect neuronal populations in number and connectivity, allowing for maturation and plasticity of the CNS. Microglia and astrocytes are part of the neurovascular unit, and together they are essential to protect and supply nutrients to the CNS. Oligodendrocytes are known for their canonical role in axonal myelination, but also contribute, with microglia and astrocytes, to CNS energy metabolism. Glial cells can achieve this variety of roles because of their heterogeneous populations comprised of different states. The neuroglial relationship can be compromised in various manners in case of pathologies affecting development and plasticity of the CNS, but also consciousness and mood. This review covers structural and functional connectivity alterations in schizophrenia, major depressive disorder, and disorder of consciousness, as well as their correlation with vascular connectivity. These networks are further explored at the cellular scale by integrating the role of glial cell diversity across the CNS to explain how these networks are affected in pathology.

A Novel Training Program to Improve Human Spatial Orientation: Preliminary Findings.

The ability to form a mental representation of the surroundings is a critical skill for spatial navigation and orientation in humans. Such a mental representation is known as a "cognitive map" and is formed as individuals familiarize themselves with the surrounding, providing detailed information about salient environmental landmarks and their spatial relationships. Despite evidence of the malleability and potential for training spatial orientation skills in humans, it remains unknown if the specific ability to form cognitive maps can be improved by an appositely developed training program. Here, we present a newly developed computerized 12-days training program in a virtual environment designed specifically to stimulate the acquisition of this important skill. We asked 15 healthy volunteers to complete the training program and perform a comprehensive spatial behavioral assessment before and after the training. We asked participants to become familiar with the environment by navigating a small area before slowly building them up to navigate within the larger and more complex environment; we asked them to travel back and forth between environmental landmarks until they had built an understanding of where those landmarks resided with respect to one another. This process repeated until participants had visited every landmark in the virtual town and had learned where each landmark resided with respect to the others. The results of this study confirmed the feasibility of the training program and suggested an improvement in the ability of participants to form mental representations of the spatial surrounding. This study provides preliminary findings on the feasibility of a 12-days program in training spatial orientation skills. We discuss the utility and potential impact of this training program in the lives of the many individuals affected by topographical disorientation as a result of an acquired or developmental condition.