Perturbing cortical networks: in vivo electrophysiological consequences of pan-neuronal chemogenetic manipulations using deschloroclozapine.

Introduction: Chemogenetic techniques, specifically the use of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), have become invaluable tools in neuroscience research. Yet, the understanding of how Gq- and Gicoupled DREADDs alter local field potential (LFP) oscillations in vivo remains incomplete. Methods: This study investigates the in vivo electrophysiological effects of DREADD actuation by deschloroclozapine, on spontaneous firing rate and LFP oscillations recorded from the anterior cingulate cortex in lightly anesthetized male rats. Results: Unexpectedly, in response to the administration of deschloroclozapine, we observed inhibitory effects with pan-neuronal hM3D(Gq) stimulation, and excitatory effects with pan-neuronal hM4D(Gi) stimulation in a significant portion of neurons. These results emphasize the need to account for indirect perturbation effects at the local neuronal network level in vivo, particularly when not all neurons express the chemogenetic receptors uniformly. In the current study, for instance, the majority of cells that were transduced with both hM3D(Gq) and hM4D(Gi) were GABAergic. Moreover, we found that panneuronal cortical chemogenetic modulation can profoundly alter oscillatory neuronal activity, presenting a potential research tool or therapeutic strategy in several neuropsychiatric models and diseases. Discussion: These findings help to optimize the use of chemogenetic techniques in neuroscience research and open new possibilities for novel therapeutic strategies.

DREADDs in Epilepsy Research: Network-Based Review.

Epilepsy can be interpreted as altered brain rhythms from overexcitation or insufficient inhibition. Chemogenetic tools have revolutionized neuroscience research because they allow "on demand" excitation or inhibition of neurons with high cellular specificity. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are the most frequently used chemogenetic techniques in epilepsy research. These engineered muscarinic receptors allow researchers to excite or inhibit targeted neurons with exogenous ligands. As a result, DREADDs have been applied to investigate the underlying cellular and network mechanisms of epilepsy. Here, we review the existing literature that has applied DREADDs to understand the pathophysiology of epilepsy. The aim of this review is to provide a general introduction to DREADDs with a focus on summarizing the current main findings in experimental epilepsy research using these techniques. Furthermore, we explore how DREADDs may be applied therapeutically as highly innovative treatments for epilepsy.

Optogenetic modulation in stroke recovery.

Stroke is one of the leading contributors to morbidity, mortality, and health care costs in the United States. Although several preclinical strategies have shown promise in the laboratory, few have succeeded in the clinical setting. Optogenetics represents a promising molecular tool, which enables highly specific circuit-level neuromodulation. Here, the conceptual background and preclinical body of evidence for optogenetics are reviewed, and translational considerations in stroke recovery are discussed.