Showing posts from September, 2015

DREADD-induced silencing disrupts the preference of female mice for opposite-sex chemosignals

Interesting paper from SFN's new on-line journal

DREADDs to deconstruct histamine action in the periphery

Interesting paper here.

New chemogenetics review


Neurologic disorders are frequently a result of inappropriate electrical and/or chemical signaling of neurons and glia. Ultimate remediation would necessitate reprogramming these signals. Historically, correcting neuronal and glial signaling is accomplished via drug therapy/administration, although they frequently fail to effectively and fully treat the underlying disorder. Developments in basic research have produced several new classes of potential therapeutics to directly and precisely control neuron activity at the single-cell level. We review one such technology, Designer Receptors Exclusively Activated by Designer Drugs, and suggest its potential as a powerful tool for augmenting neuronal and glial signaling and activity for basic and translational applications.

DREADDs to treat Parkinson's Disease

Interesting paper here.

Background Patients with advanced Parkinson's disease (PD) often present with axial symptoms, including postural- and gait difficulties that respond poorly to dopaminergic agents. Although deep brain stimulation (DBS) of a highly heterogeneous brain structure, the pedunculopontine nucleus (PPN), improves such symptoms, the underlying neuronal substrate responsible for the clinical benefits remains largely unknown, thus hampering optimization of DBS interventions. Choline acetyltransferase (ChAT)::Cre + transgenic rats were sham-lesioned or rendered parkinsonian through intranigral, unihemispheric stereotaxic administration of the ubiquitin-proteasomal system inhibitor, lactacystin, combined with designer receptors exclusively activated by designer drugs (DREADD), to activate the cholinergic neurons of the nucleus tegmenti pedunculopontine (PPTg), the rat equivalent of the human PPN. We have previously shown that the lactacystin rat model accurately reflect…

Elucidating actions of DRN 5HT neurons on behavior and circuits with DREADDS

Elucidating how the brain’s serotonergic network mediates diverse behavioral actions over both relatively short (minutes-hours) and long period of time (days-weeks) remains a major challenge for neuroscience. Our relative ignorance is largely due to the lack of technologies with robustness, reversibility and spatio-temporal control. Recently we have demonstrated that our chemogenetic approach (eg, Designer ReceptorsExclusively Activated by Designer Drugs, DREADDs) provides a reliable and robust tool for controlling genetically defined neural populations. Here we show how short- and long-term activation of dorsal raphe nucleus (DRN) serotonergic neurons induces robust behavioral responses. We found that both short- and long-term activation of DRN serotonergic neurons induce antidepressant-like behavioral responses. However, only short-term activation induces anxiogenic-like behaviors. In parallel, these behavioral phenotypes were associated with a metabolic map of whole brain network a…

GPCR-ome resource now available from ADDGENE

Our published resource now now available via ADDGENE which allows for interrogation of essentially all of the human druggable GPCR-ome.

DREADDs to deconstruct cocaine actions

Additionally, using designer receptors exclusively activated by designer drugs (DREADDs) technology, we found that stimulation of the serotonergic dorsal raphe nucleus (DRN) afferents to the nucleus accumbens (NAc) abolishes cocaine reward and promotes anti-depressive-like behaviors. Lastly, using a rat model of compulsive-like cocaine self-administration, we found that inhibition of dorsal raphe 5-HT1Aautoreceptors attenuates cocaine self-administration in rats with 6h extended access, but not 1 hour access to the drug. Therefore, our findings suggest an important role for 5-HT1A autoreceptors, and thus DRN→NAc 5-HT neuronal activity, in the etiology and vulnerability to cocaine reward and addiction. Moreover, our findings support a strategy for antagonizing 5-HT1A autoreceptors for treating cocaine addiction.

Review on using virally-mediated DREADD expression

During the past few years, CNO-sensitive designer G protein-coupled receptors (GPCRs) known as DREADDs (designer receptors exclusively activated by designer drugs) have emerged as powerful new tools for the study of GPCR physiology. In this chapter, we present protocols employing adeno-associated viruses (AAVs) to express a Gq-coupled DREADD (Dq) in two metabolically important cell types, AgRP neurons of the hypothalamus and hepatocytes of the liver. We also provide examples dealing with the metabolic analysis of the Dq mutant mice after administration of CNO in vivo. The approaches described in this chapter can be applied to other members of the DREADD family and, of course, different cell types. It is likely that the use of DREADD technology will identify physiologically important signaling pathways that can be targeted for therapeutic purposes.

Nice video of glial DREADD activation in enteric nervous system.

I get occasional questions regarding use of DREADDs outside the CNS and in non-neurons.  Here's a paper where glial localized hM3Dq was activated.  The video is pretty cool as well.

DREADDs to decostruct visceral pain

"The activity of neurons in pancreatitis-related pain centers was pharmacogenetically modulated by DREADDs, selectively and cell type-specifically expressed in target neurons using AAV-mediated gene transfer. Pharmacogenetic inhibition of PVT, but not PAG neurons attenuated visceral pain, and induced an activation of the descending inhibitory pain pathway. Activation of glutamatergic principle neurons in the mPFC, but not inhibitory neurons, also reversed visceral nociception."

Abbreviations:  the paraventricular nucleus of the thalamus (PVT), the periaqueductal grey (PAG)

CNO via osmotic minipump

I get occasional questions about this and have not tried this in my lab but was alerted to an on-line thesis which has successfully used this approach for therapeutic purposes in Alzheimer's Disease models in mice.