Chemogenetics a robust approach to pharmacology and gene therapy.

Modern developments in organic chemistry, molecular biology, virology, and genetics have opened new, exciting possibilities to better understand physiology and to create innovative, robust therapeutics. One such possibility is the burgeoning field of chemogenetics, a sub-field of chemical genetics that encompasses engineering macromolecules (particularly proteins) to modify how they interact with endogenous and exogenous ligands (particularly small molecules). Early efforts in chemogenetics were focused on parsing the function of a specific enzyme within a closely-related family by creating orthogonal enzyme-ligand pairs (e.g. kinases paired with antagonists). This powerful concept quickly expanded into engineered G-protein-coupled receptors (e.g. DREADDs/RASSL), and more recently into engineered ligand-gated ion channels (eLGIC). The modifications to the receptor focused on eliminating their activation by endogenous ligands, while preserving or enhancing their interaction with pharmacological agents (e.g. small molecule agonist). Creation of such an engineered receptor and delivering it selectively to specific cell types opens new possibilities of accurately and precisely controlling cellular activity. Control of this activity then increases our understanding of the cells function in normal physiology, while also creating the possibility of using it as a therapeutic to address pathophysiology. The DREADDs/RASSL and eLGIC approaches have been particularly impactful in neurosciences but have applications in multiple fields. In this work we introduce the history of the chemogenetic approach, review the seminal work with DREADDs/RASSLs and eLGIC, highlight the breadth of applications, and discuss the strengths and weaknesses associated with this technology, especially in the context of its development into a therapeutic.

Angiotensin type 1a receptors on corticotropin-releasing factor neurons contribute to the expression of conditioned fear.

Although generally associated with cardiovascular regulation, angiotensin II receptor type 1a (AT1a R) blockade in mouse models and humans has also been associated with enhanced fear extinction and decreased post-traumatic stress disorder (PTSD) symptom severity, respectively. The mechanisms mediating these effects remain unknown, but may involve alterations in the activities of corticotropin-releasing factor (CRF)-expressing cells, which are known to be involved in fear regulation. To test the hypothesis that AT1a R signaling in CRFergic neurons is involved in conditioned fear expression, we generated and characterized a conditional knockout mouse strain with a deletion of the AT1a R gene from its CRF-releasing cells (CRF-AT1a R((-/-)) ). These mice exhibit normal baseline heart rate, blood pressure, anxiety and locomotion, and freeze at normal levels during acquisition of auditory fear conditioning. However, CRF-AT1a R((-/-)) mice exhibit less freezing than wild-type mice during tests of conditioned fear expression-an effect that may be caused by a decrease in the consolidation of fear memory. These results suggest that central AT1a R activity in CRF-expressing cells plays a role in the expression of conditioned fear, and identify CRFergic cells as a population on which AT1 R antagonists may act to modulate fear extinction.

Voxel-based morphometry predicts shifts in dendritic spine density and morphology with auditory fear conditioning.

Neuroimaging has provided compelling data about the brain. Yet the underlying mechanisms of many neuroimaging techniques have not been elucidated. Here we report a voxel-based morphometry (VBM) study of Thy1-YFP mice following auditory fear conditioning complemented by confocal microscopy analysis of cortical thickness, neuronal morphometric features and nuclei size/density. Significant VBM results included the nuclei of the amygdala, the insula and the auditory cortex. There were no significant VBM changes in a control brain area. Focusing on the auditory cortex, confocal analysis showed that fear conditioning led to a significantly increased density of shorter and wider dendritic spines, while there were no spine differences in the control area. Of all the morphology metrics studied, the spine density was the only one to show significant correlation with the VBM signal. These data demonstrate that learning-induced structural changes detected by VBM may be partially explained by increases in dendritic spine density.

Impact of community-based instruction on the development of adaptive behavior of secondary-level students with mental retardation.

The impact of community-based instruction on the development of adaptive behavior in 34 high school students with moderate to profound mental retardation was examined. Results were: (a) Students made statistically significant gains in three of four domains of the Scales of Independent Behavior; (b) student IQ, level of student ambulation, and presence of behavior problems were not significant predictors of the amount of community-based instruction students received; and (c) the amount of community-based instruction was a more powerful predictor of gains in these domains than were IQ, level of student ambulation, and the presence of behavior problems. Results were discussed in terms of implications for the design and implementation of secondary programs for students with mental retardation.